ESC guidelines recommendations

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Review

Treatment of hypertension: The ESH/ESC guidelines recommendations Cesare Cuspidi a,b,∗ , Marijana Tadic c , Guido Grassi a,d , Giuseppe Mancia a,b a

Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy Istituto Auxologico Italiano, Milano, Italy Department of Cardiology, Charité-University-Medicine Campus Virchow Klinikum, Berlin, Germany d IRCCS Multimedica, Sesto San Giovanni, Milano, Italy b c

a r t i c l e

i n f o

Article history: Received 5 September 2017 Received in revised form 11 October 2017 Accepted 12 October 2017 Available online xxx Keywords: Hypertension guidelines Anti-hypertensive treatment Cardiovascular prevention

a b s t r a c t Effective cardiovascular prevention in the hypertensive setting needs the achievement of a tight blood pressure (BP) control with appropriate lifestyle measures and anti-hypertensive therapy. In fact, the ultimate goal of treatment strategies is the reduction of the excess of cardiovascular mortality and morbidity related to chronically elevated BP. In this chapter we will review the recommendations provided by the latest ESH/ESC guidelines focusing on the non-pharmacological and pharmacological treatment of hypertension. The first part will be focalized on the BP targets to be achieved by the treatment in the general hypertensive population and in specific clinical settings. In the second part, we will also depict the life-style changes with proven anti-hypertensive efficacy. In the third part we will describe the general principles of pharmacological therapy recommended in the general population and in special conditions. Finally we will make a brief comment on the new hypertension guidelines that will be published in 2017. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 BP targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Lifestyle changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Pharmacological therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Monotherapy and combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Treatment strategies in special conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2.1. White coat hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2.2. Masked hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2.3. Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2.4. Refractory hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Perspectives on new guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction Although the increased risk of cardiovascular disease due to arterial hypertension is a notion recognized since the introduction of blood pressure (BP) devices, the benefits of BP lowering have

∗ Corresponding autho at: Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. E-mail address: [email protected] (C. Cuspidi).

been increasingly accepted starting from the last five decades [1], since the publication of major randomized clinical trials including hundreds of thousands of hypertensive individuals. The ultimate goal of anti-hypertensive treatment is the reduction and, ideally, the abolition of the excess of cardiovascular mortality and morbidity related to chronically elevated BP. In this perspective, tight BP control in hypertensive patients is crucial to ensure optimal protection against cardiovascular complications. Over the past 20 years, major international guidelines of hypertension management have been recommending that optimal

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treatment of hypertensive patients should be based not exclusively on BP levels, but also on the precise assessment of individual total cardiovascular risk [2–5]. These recommendations have been supported by increasing evidence that only a limited fraction of the hypertensive population is affected by BP elevation alone, a large fraction presenting concurrent non-modifiable and modifiable cardiovascular risk factors. The latest 2013 ESH/ESC Guidelines recommend a simple flowchart for estimating the combined effect of various risk factors, target organ damage and comorbidities on global risk of fatal cardiovascular events [6]. Estimates take into account systolic and/or diastolic BP levels, coexistence of modifiable (smoking, dyslipidaemia, glucose intolerance, obesity) and non-modifiable (male sex, age and family history of premature cardiovascular disease) risk factors, signs of cardiac and extra-cardiac target organ damage, evidence of diabetes mellitus and established cardiovascular or renal disease. This approach allows to classify hypertensive patients at low, moderate, high and very high risk according to 10-year risk of cardiovascular mortality as suggested by 2012 ESC prevention guidelines [7]. This article is a review of the recommendations provided by the ESH/ESC guidelines [6] on a number of issues related to treatment of hypertension: 1) BP targets; 2) life-style changes, 3) pharmacological therapy (general principles, anti-hypertensive treatment in special clinical settings). Before addressing point-by-point the aforementioned topics in separate sub-sections it should be remarked that the strength of recommendations provided by guidelines is graded in three classes: I (evidence and/or general agreement that a given treatment or procedure is beneficial, useful,effective), II (conflicting evidence and/or divergence of opinion about the usefulness/efficacy of the given treatment or procedure), III (evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful). The recommendations are further classified according to different levels of evidence: A (data derived from multiple randomized trials or meta-analysis), B (data derived from single randomized clinical trial or large non-randomized studies), C (consensus or opinion of the experts and/or small studies, registries).

2. BP targets Two distinct BP targets, namely 140/90 mmHg in low-moderate risk hypertensives and <130/80 mmHg in high-risk hypertensives (i.e. subjects with diabetes, cerebrovascular, cardiovascular, or renal disease) were suggested by the 2007 ESH/ESC guidelines [5]. A re-appraisal of some of these recommendations has been made by current guidelines [6] on the basis of a an extensive review of randomized controlled trials that indicated there are no solid data supporting to lower BP to <130/80 mmHg in patients with diabetes or a history of cardiovascular or renal disease. A systolic BP target lower than 140 mmHg is currently recommended in hypertensive patients with different clinical characteristics: low-moderate cardiovascular risk (class I, level B), diabetes mellitus (class I, level A), previous stroke or ischemic transient attack, coronary heart disease, chronic kidney disease (class II, level B) and in fit elderly subjects aged <80 years (class II, level C). Systolic BP values between 150 and 140 mmHg are recommended in elderly hypertensives regardless of age, provided they are in good physical and mental conditions. Whereas, in the frail elderly population systolic BP goals should be adapted to individual tolerability. As for diastolic BP, a target of <90 mmHg is recommended in all patients, except in those with diabetes, in whom treatment optimization requires diastolic BP to be lowered to < 85 mmHg. These indications of the guidelines regarding the target pressure seems to mediate two concepts

widely debated in the last decades: 1) the lower the BP achieved by the treatment the better the outcome; 2) the hypothesis of a J-shaped relationship, according to which the total benefit of reducing BP to markedly low values are lower than for reductions to more moderate values [8,9]. Deserves mention the fact that the BP goals proposed by the guidelines refer to the pressure measured in the medical environment as no direct evidence from randomized outcome studies is yet available about BP targets when home or 24 h ambulatory BP measurements are adopted [10]. In addition to the recommendations on BP target, the 2013 ESH/ESC guidelines emphasize the concept that the protective effects of antihypertensive therapy depend not only on the BP levels achieved during treatment but also on the persistence of BP control between on-treatment visits. The first report about the clinical and prognostic role of variability visit–visit relates to hypertensive patients with coronary heart disease in which the positive effect of therapy was directly related to increasing percentage of visits with office BP at target [11]. Ten years later this remark, a meta-analysis, including a total of 23 high-quality cohort studies with 107,434 hypertensive patients, expanded the notion that the visit-to-visit variability is a strong predictor of fatal and non-fatal cardiovascular complications [12].

3. Lifestyle changes A solid body of evidence supports the view that appropriate and consistent lifestyle changes may effectively prevent hypertension in normotensive subjects, and contribute to BP reduction in hypertensive individuals already taking anti-hypertensive medications, allowing a substantial reduction of the number and doses of antihypertensive drugs. The recommended approach to nonpharmacological treatment of hypertension includes a series of behavioural changes which might result in a lower BP and the added incentive of avoiding the need for medication. The lifestyle measures recommended by the 2013 ESH/ESC guidelines are the following: 1) salt restriction, 2) moderation of alcohol consumption, 3) increased consumption of vegetables, fruit and low-fat dairy products, 4) wheight loss; 5) regular physical exercise, 6) smoking cessation. The usual salt intake is between 9 and 12 g/day in many Westernized communities and it has been shown that reduction to about 5–6 g/day has a marginal (1–2 mmHg) systolic BP-lowering effect in normotensive people and a somewhat more evident effect (4–5 mmHg) in hypertensive subjects [13,14]. A reduction in dietary sodium to 80–100 mml (about 5 g of salt) is thus recommended for the general population [15]. It has been shown that the effects of sodium reduction may vary widely in relation to individual ethnic and demographic characteristics being more greater in black people, older people and in individuals with diabetes, metabolic syndrome or chronic kidney disease. A variety of epidemiological and clinical studies suggest that light alcohol consumption may exert a favorable effects on BP levels but chronic heavy alcohol consumtion causes sustained BP elevation [16,17]. The hypertensive effect of heavy drinking occurs with all forms of alcohol (i.e. beer wine and spirits) and limitation of alcohol consumption to no more than 20–30 g of ethanol per day in men and to no more than 10–20 g of ethanol per day in women should be recommended. Hypertensive patients should be advised to consume a diet that emphasizes fruits, vegetables, low-fat dairy products, dietary and soluble fibre, whole grains, and protein from plant sources that is reduced in saturated fat and cholesterol [18]. Diet changes should be accompanied by other lifestyle measures as the long-term effects on BP of a switch to a vegetarian or reduced saturated-fat diet are somewhat inconclusive at present. Furthermore, it has been

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shown that in hypertensive patients, compared with the Dietary Approaches to Stop Hypertension (DASH) diet alone, the combination of the DASH diet with regular physical exercise and weight loss resulted in a greater reduction in BP [19]. All overweight/obese hypertensive individuals should be advised to lose weight, this is because an impressive number of trials of weight reduction as a method of BP lowering have provided favorable results about the impact of weight loss on BP levels. It deserves to be mentioned, however, that the extent of BP fall has varied markedly between studies [20]. In a meta-analysis by Neter et al. [21] including twenty-five randomized, controlled trials with a total of 4874 participants, the mean systolic BP and diastolic BP reductions associated with an average weight loss of 5.1 kg were 4.4 mmHg and 3.6 mmHg, respectively. Further data have led to the popular notion that for each kilogram of weigth lost, a 1 mmHg reduction of systolic and diastolic BP can be achieved. Consequently, maintenance of a healthy body weight (body mass index of about 25 kg/m2 ) is generally recommended for normotensive individuals to prevent hypertension and for hypertensive patients to improve the efficacy of antihypertensive medications and the cardiovascular risk profile. Higher fitness level is associated with lower probability and incidence of hypertension. Several randomized trials have assessed the hypotensive effect of physical exercise suggesting a small but useful reduction in BP. A meta-analysis of 54 randomized controlled trials with 2419 participants showed that aerobic exercise was associated with a significant reduction in systolic BP and diastolic BP (3.8 and 2.6 mmHg, respectively) [22]. The health benefits resulting from physical exercise depend on the type and regularity and include improvements in glucose and lipid metabolism. In this regard, the guidelines recommend regular moderate dynamic exercise (i.e. walking, jogging, cycling or swimming at least 30 min on 5–7 days per week). Smoking leads to an acute increase in BP and heart rate, persisting for more than 15 min after smoking one cigarette, as a consequence of a powerful stimulation of the sympathetic nervous system [23]. Studies using ambulatory BP monitoring (ABPM) have shown that smoking is a key correlate of masked hypertension. In fact, day-time BP values have been reported to be significantly higher in smokers than in non smokers, whereas office and nighttime values did not differ between the two groups [24]. Beside the direct influence on BP values, smoking is the most important modifiable cardiovascular risk factor and smoking cessation is probably the single most effective lifestyle measure for the prevention of cardiovascular morbidity and mortality in the general population. Although the hypotensive effects of non-pharmacological measures have been well documented (class I, level A), it should be remarked that their benefits in terms of cardiovascular prevention have not been sufficiently tested (level B) and large randomized prospective studies are needed. Furthemore, their BP lowering effects are lower compared to drug therapy with a wide betweenpatients variability in the response. Finally, another important limitation of non-pharmacological approach is represented by poor compliance to these measures in the medium and long term period.

4. Pharmacological therapy Indisputable evidence is available that antihypertensive treatment reduces the elevated incidence of cardiovascular morbid and fatal events related to high BP [25]. Evidence is also available that the main benefits of antihypertensive treatment are due to lowering of BP per se and are largely independent of the drugs employed [26,27]. The 2013 ESH/ESC guidelines reiterating previous indications [4,5] confirm that five classes of drugs such as: 1) diuretics, 2) beta-blockers, 3) calcium antagonists, 4) angiotensin converting

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enzyme (ACE) inhibitors and 5) angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations. It is important to note that the guidelines state clearly that there are no solid scientific elements that allow to classify the various classes of medications in a hierarchical order of efficacy. This is because the effects on cause-specific outcomes of the various agents are similar or differ marginally, the type of outcome in a given patient is unpredictable, and all classes of antihypertensive drugs have their clinical advantages but also contra-indications. Identification of the drug to be used as first-step antihypertensive treatment has always been, and remains, a matter of debate. The decision wihich drug (or drug combination) to choose as firstline therapy depend on many variables such as coexisting metabolic disorders, obesity, presence of subclinical organ damage and cardiovascular disease [28]. The general criteria on wihich to base a rational selection of a given drug can be summarized as follows. First, in a patient with a history of anti-hypertensive treatment previous favorable or unfavorable effects in terms of efficacy and tolerability of a given drug class should be taken into account. A second important issue refers to the effect of drugs on cardiovascular risk factors in relation to the cardiovascular risk profile of the individual patient. Third, the presence of subclinical organ damage, renal disease, cerebrovascular disease or diabetes should direct the doctor to the choice of drugs which have been reported to be more effective than others in these specific conditions. Fourth, particular attention should be paid to the presence of coexisting non cardiovascular diseases, because their treatment may interfere with anti-hypertensive drugs. Finally, it should be noted that the cost of drugs may represent an important variable that could compromise therapeutic compliance of the patients. 4.1. Monotherapy and combination therapy An antihypertensive treatment strategy based on an initial monotherapy at an effective dose followed, if BP control is not achieved, by the addition of other drugs is deemed to be correct by guidelines. The main advantage of initiating treatment with monotherapy is that of using a single agent, thus being able to refer effectiveness and adverse effects to that specific agent (Table 1) A further advantage relates to limiting the risk of an excessive BP reduction in some patients where there has been an overestimate of actual BP. The main limitation of mono-therapy is represented by the evidence that it can effectively reduce BP in only a limited number of hypertensive patients and that most patients require the

Table 1 Possible combinations of antihypertensive drug classes. PREFERRED ACE-inhibitors and thiazide diuretics ACE-inhibitors and calcium antagonists Angiotensin-receptor blockers and thiazide diuretics Angiotensin-receptor blockers and calcium antagonists Calcium antagonists and thiazide diuretics USEFUL WITH SOME LIMITATIONS Thiazide diuretics and beta-blockers POSSIBLE BUT LESS WELL TESTED ACE-inhibitors and beta-blockers ACE-inhibitors and other anti-hypertensives Angiotensin-receptor blockers and beta-blockers Angiotensin-receptor blockers and other anti-hypertensives Calcium antagonists and beta-blockers Calcium antagonists and other anti-hypertensives Thiazide diuretics and other anti-hypertensives NOT RECOMMEDED ACE-inhibitors and angiotensin-receptor blockers

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Fig. 1. Monotherapy versus drug combination strategies to achieve target blood pressure (2013 ESH/ESC guidelines).

combination of at least two drugs to achieve BP control. The strategy of switching from one monotherapy to another in the hope to find the monotherapy which controls BP and thus avoid use of multiple drugs may be a painstaking procedure and discourage adherence. The ability of any monotherapy to control BP is limited, presumably because a single mechanism of action is often ineffective against a multiregulated variable such as BP. This pathophysiological consideration is supported by a large body of clinical evidence. A meta-analysis of more than 40 studies has shown that combining two agents from any two classes of antihypertensive drugs increases the BP reduction much more than increasing the dose of one single agent [29]. The advantages of combination therapy are not merely restricted to more pronounced hypertensive effects. By using a two-drug combination as first-step treatment, either combination component can be administered in the low dose range, which is more likely to be free of side effects compared to full dose monotherapy. This can be very important in encouraging adherence to therapy and ultimately in improving the prevention of cardiovascular events. The use of a rational combination of medications may also limit the mechanisms of counter-regulation induced by a single drug. Starting treatment with a combination may allow BP targets to be achieved earlier than with monotherapy which is potentially beneficial in high-risk patients and provide a greater probability of achieving the target BP in patients with higher BP values. The issue of debate is whether combination therapy should always be preceded by an attempt to use monotherapy, or whether and when combination therapy may be regared as the initial approach. Initial monotherapy may be preferred when hypertension is mild and the total cardiovascular risk not high or very high. On the other hand, combination therapy as a first step may be indicated in patients with a marked BP elevation and a high or very high cardiovascular risk.

Finally, when starting with monotherapy or with a two-drug combination, doses can be stepped up if necessary to gain the BP target; if the target is not achieved by a two-drug combination at full doses, switching to different two-drug combination can be considered or a third agent added (Fig. 1). The debate about the real advantages of fixed combinations than the extemporaneous ones lasts for many years. The most obvious merit of extemporaneous combinations is flexibility. Another potential advantage is that when drugs are given separately their role in the onset of side effects can be more easily ascertained. Nevertheless the guidelines support the use of combinations of two antihypertensive drugs at fixed doses in a single tablet, because reducing the number of pills to be taken daily improves adherence [30,31]. Of note, the increasing use of fixed combinations reduces the risk of use of non-rational extemporaneous combinations (Table 2). Most fixed two-drug combinations are now provided at different doses, which minimizes one of its limits, namely the inability to increase the dose of one drug independently of the other. This also the case also for fixed-dose combinations of three drugs (i.e. a blocker of the RAS, a calcium antagonist and a diuretic), which are increasingly becoming available worldwide [32]. 4.2. Treatment strategies in special conditions The 2013 ESH/ESH guidelines [6] give specific therapeutic indications for 14 different demographic/clinical conditions: white coat hypertension (WCH), masked hypertension (MH), elderly, young adults, women, diabetes mellitus, metabolic syndrome, obstructive sleep apnea, diabetic and non-diabetic nephropaty, cerebrovascular disease, heart disease, atherosclerosis, sexual dysfunction and refractory hypertension.

Table 2 Two drug combinations as initial anti-hypertensive treatment. CONS

PROS

One of the two drugs may be ineffective.

When one agent ineffective, finding an alternative monotherapy may be a painstaking process, adversely affecting compliance. Prompter response in a larger number of patients (benefit in high risk patients?). Lower drop-out rate.

Ascribing side effects more difficult. Risk of excessive blood pressure fall.

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In this section, however, we will focus our attention only on some of these issues, and our selection of topics was motivated by the following motivations: 1) therapeutic aspects of some of the aforementioned conditions such as WCH and MH are still largely debated and still lacking solid evidence; 2) the impressive increase in life expectancy makes hypertension in the elderly a topical therapeutic problem with outstanding clinical and social implications; 3) refractory hypertension is a very complex clinical condition that needs the referral of these high-risk patients in specialist centres. For the other special conditions mentioned above see Mancia et. [6]. 4.2.1. White coat hypertension The management of WCH (elevated office BP during repeated visits concomitant with normal out-of-office BP values, as assessed by home and/or 24-h ambulatorory BP monitoring measurements) should include an accurate assessment of the gobal cardiovacular risk [33,34]. Variables such as hypertension grade, risk factors and associated diseases may be easily evaluated by clinical evaluation and routine examinations; whereas detection of target organ damage mostly depends on sensitivity of diagnostic tools [35,36]. Although evidence-based data on therapeutic management of WCH are lacking the 2013 ESH/ESC guidelines suggest that in WCH individuals without additional cardiovascular risk factors, intervention may be limited to effective lifestyle changes, such as reduction of salt intake, wheight loss, regular aerobic physical activity, and smoking cessation (class II, level C) (Table 3). This integrated approach has to be associated to a close clinical and laboratory follow-up including regular home BP measurements and periodical ABPM. This is because WCH subjects have an increased risk of developing metabolic abnormalities (i.e. metabolic syndrome or diabetes) and to progress to sustained hypertension. The likelihood of shifting from WCH to sustained hypertension has been shown to be high in subjects with out-of-office BP values in the upper normal range [37]. In WCH individuals at high- or very-high cardiovascular risk, due to the presence of multiple risk factors, type 2 diabetes mellitus, renal dysfunction, any prognostically validated markers of target organ damage (electrocardiographic or echocardiographic LVH, carotid IM thickening, plaque, microalbuminuria, increased pulse wave velocity) and cardiovascular disease drug treatment may be considered in addition to appropriate lifestyle measures (class II, level C). 4.2.2. Masked hypertension Increasing evidence supports the view that MH (normal office and elevated out-of −office BP) is a BP phenotype associated with increased risk of fatal and non-fatal cardiovascular events as compared to true normotension and close to that of sustained hypertension [38,39]. Several aspects concerning MH are still debated, in particular controversy exists about methods (i.e. home

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versus ambulatory BP) more reliably detecting subjects with elevated BP out of the office environment, about MH actual prevalence in the general population, its clinical correlates and reproducibility over time [40,41]. Although literature findings on demographic and clinical correlates of MH are inconclusive, it is conceivable that sympathetic activation triggered by stress, anxiety, job or physical activity, smoking, alcohol consumption, sleep apnoea plays a central role in subjects with MH. Tailored interventions on life-style aimed at treating the modifiable risk factors associated with MH including obesity, diabetes, stress, sleep apnea, and avoidance of smoking and alcohol abuse are strongly recommended by current hypertension guidelines (class II, level C). A further recommended strategy in managing MH is the reduction of ambulatory BP (or home BP) using anti-hypertensive drugs, despite the presence of normal office BP, and then perform periodic ABPM to assess on-treatment ambulatory or home BP (class II, level C). 4.2.3. Elderly All hypertensive agents are recommended and can be used in the elderly (class I, level A), after having carefully considered the possible controindications related to presence of concomitant diseases and their therapies. This is because randomized controlled trials aimed to investigate the effects of BP lowering on cardiovascular outcomes in the elderly provided clear evidence in favour of diuretics, beta-blockers, calcium antagonists, ACE inhibitors,and angiotensin receptor blockers [42–46]. As for the isolated systolic hypertension, probably the most common type of hypertension in elderly and very elderly subjects, the evidence available is in support of the protective efficacy of diuretics and calcium channel blockers that may preferred in this condition (class I, level A) [47–49]. Two other points need to be briefly mentioned. First, there is no evidence that different classes are differently effective in the older versus the younger patient. Second, trials addressing the beneficial effects of the antihypertensive therapy in the very elderly (older than 80 years) included only subjects in good physical and mental conditions and excluded ill and frail individuals [42]. 4.2.4. Refractory hypertension Hypertension is defined as resistant or refractory to treatment when a therapeutic strategy that includes effective lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses is unable to lower BP values to <140/90 mmHg [50]. The prevalence of refractory hypertension varies widely in relation to demographic and clinical characteristics of the population tested. True refractory hypertension is estimated to be less than 5% in the general hypertensive population [51,52]. A correct diagnostic approach to this condition requires detailed information on the patient’s history, an accurate physical examination, and appropriate laboratory tests to detect

Table 3 Flow chart summarizing the therapeutic approach in white coat hypertensive individuals according their cardiovascular risk profile.

Class II a, level C. Class II b, level C.

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associated risk factors, target organ damage and secondary causes of hypertension. Furthermore, ABPM should be performed to rule out spurious resistence and quantify to a better degree the BP elevation. In most cases, this complex clinical work-up needs to be performed in a specialist centre. Intervention and observational studies have provided evidence that all drug classes with mechanisms of action different from those of the existing three-drug combination can lower BP. An improvement in BP control has been reported from the use of mineralcorticoid receptor antagonists (spironolactone, eplerenone), the alfa-blocker, doxazosin and a further increase in diuretic dose, loop diuretics replacing thiazides or chorthalidone if renal function is impaired. In case of ineffectiveness of drug treatment invasive procedures such as renal denervation [53,54] may be considered (class II, level C). Renal denervation and related procedures should be reserved to truly resistant hypertensive patients with office BP values ≥ 160/110 mmHg and elevated ambulatory BP (class I, level C).

5. Perspectives on new guidelines Cardiovascular prevention in the hypertensive setting needs to be greatly improved through tight control of BP with appropriate lifestyle measures and anti-hypertensive therapy. To achieve this ambitious but feasible goal, many topics of uncertainty need to be investigated and resolved with reliable scientific evidence. Some issues that need answers are briefly summarized from these questions: 1) what are the optimal office and out-office systolic and diastolic BP values to reach by treatment? this topic is particularly relevant in the light of the findings of some recent trials [55,56]; 2) should elderly subjects with a systolic BP between 140 and 160 mmHg be given BP lowering drugs? 3) should drug treatment be given to subjects with pre-hypertension and WCH? and if so, in which patients? These and other topics, especially optimal treatment goals in different clinical settings, the role of treatment with the combination of the two drugs as a first step, drug treatment in grade 1 low risk hypertension, WCH and pre-hypertension, how to treat resistant hypertension, will be addressed in the forthcoming new hypertension guidelines scheduled to be released in 2017 by the ESH/ESC and, jointly by the American College of Cardiology and the American Heart Association (AHA). These guidelines will serve as an update to the hypertension guidelines released by the ESH/ESC in 2013 and by the Eighth Joint National Committee (JNC 8) in 2014, respectively. Results from many recent clinical trials and analyses–most notably from the Systolic Blood Pressure Intervention Trial (SPRINT) [55] are expected to form the basis of these new guidelines, which should address, as mentioned above, new hypertension treatment goals and new approaches to the treatment of the elderly, among other recommendations. It is hard to point out in this regard that the SPRINT Research Group randomly assigned 9361 persons with a systolic BP of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic BP target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, ordeath from cardiovascular causes. The trials was stopped early after a median follow-up of 3 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group (-25%) than in the standard-treatment group. What will impact the results of the Sprint study in defining optimal BP targets by the new guidelines is still unclear. This is because

1) noteworthy patient populations were excluded from the trial (including those under the age of 50 years, those with diabetes, and those who had previously had a stroke); 2) major correction factors need to be applied to the unattended automatic office BP values to make them confrontable with those measured in all other randomized trials upon which guidelines have based their target BP recommendations [57]. References [1] Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg, JAMA 202 (1967) 1028–1034. [2] Guidelines Subcommittee 1999, World Health Organization-international society of hypertension guidelines for the management of hypertension, J. Hypertens. (17) (1999) 151–183. 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