5.2.2 Monotherapy and combination therapy
22.214.171.124 Pros and cons of the two approaches
The 2007 ESH/ESC Guidelines underlined that, no matter which drug is employed, monotherapy can effectively reduce BP in only a limited number of hypertensive patients and that most patients require the combination of at least two drugs to achieve BP control . Therefore, the issue is not whether combination therapy is useful, but whether it should always be preceded by an attempt to use monotherapy, or whether—and when—combination therapy may be the initial approach.
The obvious advantage of initiating treatment with monotherapy is that of using a single agent, thus being able to ascribe effectiveness and adverse effects to that agent. The disadvantages are that, when monotherapy with one agent is ineffective or insufficiently effective, finding an alternative monotherapy that is more effective or better tolerated may be a painstaking process and discourage adherence. Additionally, 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 agent . The advantage of initiating with combination therapy is a prompter response in a larger number of patients (potentially beneficial in high-risk patients), a greater probability of achieving the target BP in patients with higher BP values, and a lower probability of discouraging patient adherence with many treatment changes. Indeed, a recent survey has shown that patients receiving combination therapy have a lower drop-out rate than patients given any monotherapy . A further advantage is that there are physiological and pharmacological synergies between different classes of agents, that may not only justify a greater BP reduction but also cause fewer side-effects and may provide larger benefits than those offered by a single agent. The disadvantage of initiating with drug combinations is that one of the drugs may be ineffective.
On the whole the suggestion, given in the 2007 ESH/ESC Guidelines , of considering initiation with a drug combination in patients at high risk or with markedly high baseline BP can be reconfirmed.
When initiating with monotherapy or with a two-drug combination, doses can be stepped up if necessary to achieve the BP target; if the target is not achieved by a two-drug combination at full doses, switching to another two-drug combination can be considered or a third drug added. However, in patients with resistant hypertension, adding drugs to drugs should be done with attention to results and any compound overtly ineffective or minimally effective should be replaced, rather than retained in an automatic step-up multiple-drug approach (Fig. 3).
126.96.36.199 Preferred drug combinations
Only indirect data are available from randomized trials giving information on drug combinations effective in reducing CV outcomes. Among the large number of RCTs of antihypertensive therapy, only three systematically used a given two-drug combination in at least one arm: the ADVANCE trial compared an ACE inhibitor and diuretic combination with placebo (but on top of continued background therapy) , FEVER compared a calcium antagonist and diuretic combination with diuretic alone (plus placebo)  and ACCOMPLISH compared the same ACE inhibitor in combination with either a diuretic or a calcium antagonist . In all other trials, treatment was initiated by monotherapy in either arm and another drug (and sometimes more than one drug) was added in some patients. In some trials, the second drug was chosen by the investigator among those not used in the other treatment arms, as in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack (ALLHAT) .
With this important reservation, Table 16 shows that, with the exception of an angiotensin receptor blocker and a calcium antagonist (never systematically used in an outcome trial), all combinations were used in at least one active arm of placebo-controlled trials in which the active arm was associated with significant benefit [269,276,287,296,449–454]. In trials comparing different regimens, all combinations have been used in a larger or smaller proportion of patients, without major differences in benefits [186,445,448,455,456,458–461]. The only exceptions are two trials in which a large proportion of the patients received either an angiotensin receptor blocker-diuretic combination or a calcium antagonist-ACE inhibitor combination [423,457], both of which were superior to a beta-blocker-diuretic combination in reducing CV events. Admittedly, a beta-blocker-diuretic combination was as effective as other combinations in several other trials [448,455,460,461], and more effective than placebo in three trials [449,453,454]. However, the beta-blocker- diuretic combination appears to elicit more cases of new-onset diabetes in susceptible individuals, compared with other combinations .
The only trial directly comparing two combinations in all patients (ACCOMPLISH)  found significant superiority of an ACE inhibitor-calcium antagonist combination over the ACE inhibitor-diuretic combination despite there being no BP difference between the two arms. These unexpected results deserve to be repeated, because trials comparing a calcium antagonist-based therapy with a diuretic-based therapy have never shown superiority of the calcium antagonist. Nonetheless, the possibility that ACCOMPLISH results may be due to a more effective reduction of central BP by the association of an RAS blocker with a calcium antagonist deserves to be investigated [398,399,464].
The only combination that cannot be recommended on the basis of trial results is that between two different blockers of the RAS. Findings in ONTARGET [331,463], that the combination of an ACE inhibitor and an angiotensin receptor blocker are accompanied by a significant excess of cases of ESRD, have recently been supported by the results of the ALTITUDE trial in diabetic patients . This trial was prematurely interrupted because of an excess of cases of ESRD and stroke in the arm in which the renin inhibitor aliskiren was added to preexisting treatment using an ACE inhibitor or an angiotensin receptor blocker. It should be noted, however, that BP was less closely monitored for hypotension in ALTITUDE. Two-drug combinations most widely used are indicated in the scheme shown in Fig. 4.
188.8.131.52 Fixed-dose or single-pill combinations
As in previous guidelines, the 2013 ESH/ESC Guidelines favour 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, which is unfortunately low in hypertension, and increases the rate of BP control [465,466]. This approach is now facilitated by the availability of different fixed-dose combinations of the same two drugs, which minimizes one of its inconveniences, namely the inability to increase the dose of one drug independently of the other. This holds also for fixed- dose combinations of three drugs (usually a blocker of the RAS, a calcium antagonist and a diuretic), which are increasingly becoming available. Availability extends to the so-called polypill (i.e. a fixed-dose combination of several antihypertensive drugs with a statin and a low-dose aspirin), with the rationale that hypertensive patients often present with dyslipidaemia and not infrequently have a high CV risk [12,13]. One study has shown that, when combined into the polypill, different agents maintain all or most their expected effects . The treatment simplification associated with this approach may only be considered, however, if the need for each polypill component has been previously established .
5.2.3 Summary of recommendations on treatment strategies and choice of drugs
Treatment strategies and choice of drugs
6. TREATMENT STRATEGIES IN SPECIAL CONDITIONS
6.1 White-coat hypertension
If the evidence favouring drug treatment in grade 1 hypertensives at low-to-moderate risk is scant (see Section 4.2.3), evidence is even weaker in white-coat hypertensives. In these individuals, no randomized trial has ever investigated whether administration of BP-lowering drugs leads to a reduction in CV morbid and fatal events. To date, information is largely limited to a subgroup analysis of the SYSTolic Hypertension in Europe (SYSTEUR) trial, which concluded that drug treatment reduces ambulatory BP and CV morbidity and mortality less in white-coat than in sustained hypertensive individuals, based on a small number of events .
The following considerations may help orientating the therapeutic decision in individual cases. Subjects with white-coat hypertension may frequently have dysmetabolic risk factors and some asymptomatic OD (see Section 3.1.3), the presence of which raises CV risk. In these higher-risk individuals with white-coat hypertension, drug treatment may be considered in addition to appropriate lifestyle changes. Both lifestyle changes and drug treatment may be considered also when normal ambulatory BP values are accompanied by abnormal home BP values (or vice versa) because this condition is also characterized by increased CV risk . In the absence of additional CV risk factors, intervention may be limited to lifestyle changes only, but this decision should be accompanied by a close follow-up of the patients (including periodical out-of-office BP monitoring) because, in white-coat hypertensive subjects, out-of-office BP is often higher than in truly normotensive subjects and white-coat hypertensives have a greater risk of developing OD and to progress to diabetes and sustained hypertension (see Section 3.1.3). Consideration should also be given to the fact that, because of its high prevalence (particularly in mild-to-moderate hypertension), white-coat hypertension was presumably well represented in antihypertensive drug trials that have established clinic BP reduction as the guidance for treatment. Recommendations on treatment strategies in white-coat hypertension are listed below.
6.2 Masked hypertension
Isolated ambulatory or masked hypertension is infrequently diagnosed because finding a normal clinic BP only exceptionally leads to home or ambulatory BP measurements. When this condition is identified, however, both lifestyle measures and antihypertensive drug treatment should be considered because masked hypertension has consistently been found to have a CV risk very close to that of in-office and out-of-office hypertension [109,112,117,469]. Both at the time of treatment decision and during follow-up, attention to dysmetabolic risk factors and OD should be considered since these conditions are much more common in masked hypertension than in normotensive individuals. Efficacy of antihypertensive treatment should be assessed by ambulatory and/or home BP measurements.
6.2.1 Summary of recommendations on treatment strategies in white-coat and masked hypertension
Treatment strategies in white-coat and masked hypertension
In previous sections (4.2.5 and 4.3.3) we mentioned that there is strong evidence of benefits from lowering of BP by antihypertensive treatment in the elderly, limited to individuals with initial SBP of >160 mmHg, whose SBP was reduced to values <150 but not <140 mmHg. Therefore the recommendation of lowering SBP to <150 mmHg in elderly individuals with SBP >160 mmHg is strongly evidence-based. However, at least in elderly individuals younger than 80 years, antihypertensive treatment may be considered at SBP values >140 mmHg and aimed at values <140 mmHg, if the individuals are fit and treatment is well tolerated.
Direct evidence of the effect of antihypertensive treatment in elderly hypertensives (older than 80 years) was still missing at the time the 2007 ESH/ESC Guidelines were prepared. The subsequent publication of the HYpertension in the Very Elderly Trial (HYVET) results , comparing active treatment (the diuretic indapamide supplemented, if necessary, by the ACE inhibitor perindopril) with placebo in octogenarians with entry SBP >160 mmHg, reported a significant reduction in major CV events and all-cause deaths by aiming at SBP values <150 mmHg (mean achieved SBP: 144 mmHg). HYVET deliberately recruited patients in good physical and mental conditions and excluded ill and frail individuals, who are so commonplace among octogenarians, and also excluded patients with clinically relevant orthostatic hypotension. The duration of follow-up was also rather short (mean: 1.5 years) because the trial was interrupted prematurely by the safety monitoring board.
RCTs that have shown beneficial effects of antihypertensive treatment in the elderly have used different classes of compounds and so there is evidence in favour of diuretics [287,449,454,470,471], beta-blockers [453,454], calcium antagonists [451,452,460], ACE inhibitors , and angiotensin receptor blockers . The three trials on isolated systolic hypertension used a diuretic  or a calcium antagonist [451,452].
A prospective meta-analysis compared the benefits of different antihypertensive regimens in patients younger or older than 65 years and confirmed that there is no evidence that different classes are differently effective in the younger vs. the older patient .
6.3.1 Summary of recommendations on antihypertensive treatment strategies in the elderly
Antihypertensive treatment strategies in the elderly
6.4 Young adults
In young adults with moderately high BP it is almost impossible to provide recommendations based directly on evidence from intervention trials, since outcomes are delayed by a period of years. The results of an important observational study on 1.2 million men in Sweden, initially investigated at a mean age of 18.4 years at the time of military conscription examination and followed-up for a median of 24 years, have recently been reported . The relationship of SBP to total mortality was U-shaped with a nadir at approximately 130 mmHg, but the relationship with CV mortality increased monotonically (the higher the BP the higher the risk). In these young men (without stiff, diseased arteries) the relationship of DBP to total and CV mortality was even stronger than that of SBP, with an apparent threshold around 90 mmHg. Approximately 20% of the total mortality in these young men could be explained by their DBP. Young hypertensives may sometimes present with an isolated elevation of DBP. Despite absence of RCT evidence on the benefits of antihypertensive treatment in these young individuals, their treatment with drugs may be considered prudent and, especially when other risk factors are present, BP should be reduced to <140/90 mmHg. The case may be different for young individuals in whom brachial SBP is elevated with normal DBP values (<90 mmHg). As discussed in sections 3.1.6 and 4.2.4 these individuals sometimes have a normal central SBP, and can be followed with lifestyle measures only.
The representation of women in RCTs in hypertension is 44% , but only 24% of all CV trials report sex-specific results [474–475]. A subgroup analysis by sex of 31 RCTs including individuals found similar BP reductions for men and women and no evidence that the two genders obtain different levels of protection from lowering of BP, or that regimens based on ACE inhibitors, calcium antagonists, angiotensin receptor blockers or diuretics/beta-blockers were more effective in one sex than the other .
In women with child-bearing potential, ACE inhibitors and angiotensin receptor blockers should be avoided, due to possible teratogenic effects. This is the case also for aliskiren, a direct renin inhibitor, although there has not been a single case report of exposure to aliskiren in pregnancy.
6.5.1 Oral contraceptives
Use of oral contraceptives (OCs) is associated with some small but significant increases in BP and with the development of hypertension in about 5% of users [476,477]. Notably, these studies evaluated older-generation OCs, with relatively higher oestrogen doses compared with those currently used (containing <50 mg oestrogen, ranging most often from 20–35 mg of ethinyl estradiol and a low dose of second- or third-generation progestins). The risk of developing hypertension decreased quickly with cessation of OCs and past users appeared to have only a slightly increased risk . Similar results were later shown by the Prevention of REnal and Vascular ENdstage Disease (PREVEND) study in which second- and third- generation OCs were evaluated separately : in this study, after an initial increase, urinary albumin excretion fell once OC therapy had been stopped. Drospirenone (3 mg), a newer progestin with an antimineralocorticoid diuretic effect, combined with ethinyl estradiol at various doses, lowered SBP by 1–4 mmHg across the groups . Unfortunately, there is growing evidence that drospirenone is associated with a greater risk of venous thrombo-embolism than levonorgestrel (a second-generation synthetic progestogen) .
The association between combined OCs and the risk of myocardial infarction has been intensively studied and the conclusions are controversial. Earlier prospective studies consistently showed an increased risk of acute myocardial infarction among women who use OCs and particularly in OC users who smoke, and extended this observation to past smokers on OCs . Two case-control studies using the second- and third-generation OCs exist, but with conflicting results [482,483]. A large-scale, Swedish, population-based, prospective study, in which most of the current OC users were taking low-dose oestrogen and second- or third-generation progestins, did not find use of OCs to be associated with an increased risk of myocardial infarction . Data from observational studies with progestogen-only OCs suggest no increase in risk of myocardial infarction .
Three separate meta-analyses summarizing over 30 years of studies have shown that OC users have about a two-fold increased risk of stroke over nonusers [486–488]. In an Israeli population-based cohort study, drospirenone-containing OCs were not associated with an increased risk of TIAs and stroke .
There are no outcome data on the newest non-oral formulations of hormone contraception (injectable, topical, vaginal routes). However, transdermal patches and vaginal rings have been found to be associated with an increased risk of venous thrombosis, compared with age-matched controls .
Although the incidence of myocardial infarction and ischaemic stroke is low in the age group of OC users, the risk of OCs is small in absolute terms but has an important effect on women's health, since 30–45% of women of reproductive age use OCs. Current recommendations indicate that OCs should be selected and initiated by weighing risks and benefits for the individual patient . BP should be evaluated using properly taken measurements and a single BP reading is not sufficient to diagnose hypertension . Women aged 35 years and older should be assessed for CV risk factors, including hypertension. It is not recommended that OCs be used in women with uncontrolled hypertension. Discontinuation of combined OCs in women with hypertension may improve their BP control . In women who smoke and are over the age of 35 years, OCs should be prescribed with caution .
6.5.2 Hormone replacement therapy
Hormone replacement therapy (HRT) and selective oestrogen receptor modulators should not be used for primary or secondary prevention of CVD . If occasionally treating younger, perimenopausal women for severe menopausal symptoms, the benefits should be weighed against potential risks of HRT [490,496]. The probability is low that BP will increase with HRT in menopausal hypertensive women .
Hypertensive disorders in pregnancy have been reviewed recently by the ESC Guidelines on the management of CVD during pregnancy , and by other organizations . In the absence of RCTs, recommendations can only be guided by expert opinion. While there is consensus that drug treatment of severe hypertension in pregnancy (>160 for SBP or >110 mmHgfor DBP) is required and beneficial, the benefits of antihypertensive therapy are uncertain for mildly to moderately elevated BP in pregnancy (<160/110 mmHg), either preexisting or pregnancy-induced, except for a lower risk of developing severe hypertension . International and national guidelines vary with respect to thresholds for starting treatment and BP targets in pregnancy. The suggestion, in the 2007 ESH/ESC Guidelines , of considering drug treatment in all pregnant women with persistent elevation of BP >150/95 mmHg is supported by recent US data, which show an increasing trend in the rate of pregnancy-related hospitalizations with stroke—especially during the postpartum period—from 1994 to 2007 , and by an analysis of stroke victims with severe preeclampsia and eclampsia . Despite lack of evidence, the 2013 Task Force reconfirms that physicians should consider early initiation of antihypertensive treatment at values >140/90 mmHg in women with (i) gestational hypertension (with or without proteinuria), (ii) preexisting hypertension with the superimposition of gestational hypertension or (iii) hypertension with asymptomatic OD or symptoms at any time during pregnancy.
No additional information has been provided, after publication of the previous Guidelines , on the antihypertensive drugs to be used in pregnant hypertensive women: therefore the recommendations to use methyldopa, labetalol and nifedipine as the only calcium antagonist really tested in pregnancy can be confirmed. Beta-blockers (possibly causing foetal growth retardation if given in early pregnancy) and diuretics (in preexisting reduction of plasma volume) should be used with caution. As mentioned above, all agents interfering with the renin-angiotensin system (ACE inhibitors, ARBs, renin inhibitors) should absolutely be avoided. In emergency (preeclampsia), intravenous labetalol is the drug of choice with sodium nitroprusside or nitroglycerin in intravenous infusion being the other option.
There is a considerable controversy regarding the efficacy of low-dose aspirin for the prevention of preeclampsia. Despite a large meta-analysis reporting a small benefit of aspirin in preventing preeclampsia , two other very recent analyses came to opposing conclusions. Rossi and Mullin used pooled data from approximately 5000 women at high risk and 5000 at low risk for preeclampsia and reported no effect of low-dose aspirin in the prevention of the disease . Bujold et al. , however, pooled data from over 11 000 women enrolled in RTCs of low-dose aspirin in pregnant women and concluded that women who initiated treatment at <16 weeks of gestation had a significant and marked reduction of the relative risk for developing preeclampsia (relative risk: 0.47) and severe preeclampsia (relative risk: 0.09) compared with control . Faced with these discrepant data, only prudent advice can be offered: women at high risk of preeclampsia (from hypertension in a previous pregnancy, CKD, autoimmune disease such as systemic lupus erythematosus, or antiphospholipid syndrome, type 1 or 2 diabetes or chronic hypertension) or with more than one moderate risk factor for preeclampsia (first pregnancy, age >40 years, pregnancy interval of >10 years, BMI >35 kg/m2 at first visit, family history of preeclampsia and multiple pregnancy), may be advised to take 75 mg of aspirin daily from 12 weeks until the birth of the baby, provided that they are at low risk of gastrointestinal haemorrhage.
6.5.4 Long-term cardiovascular consequences in gestational hypertension
Because of its CV and metabolic stress, pregnancy provides a unique opportunity to estimate a woman's lifetime risk; preeclampsia may be an early indicator of CVD risk. A recent large meta-analysis found that women with a history of preeclampsia have approximately double the risk of subsequent ischaemic heart disease, stroke and venous thrombo-embolic events over the 5–15 years after pregnancy . The risk of developing hypertension is almost four-fold . Women with early-onset preeclampsia (delivery before 32 weeks of gestation), with stillbirth or foetal growth retardation are considered at highest risk. Risk factors before pregnancy for the development of hypertensive disorders are high maternal age, elevated BP, dyslipidaemia, obesity, positive family history of CVD, antiphospholipid syndrome and glucose intolerance. Hypertensive disorders have been recognized as an important risk factor for CVD in women . Therefore lifestyle modifications and regular check-ups of BP and metabolic factors are recommended after delivery, to reduce future CVD.
6.5.5 Summary of recommendations on treatment strategies in hypertensive women
Treatment strategies in hypertensive women
6.6 Diabetes mellitus
High BP is a common feature of both type 1 and type 2 diabetes and masked hypertension is not infrequent , so that monitoring 24-h ambulatory BP in apparently normotensive patients with diabetes may be a useful diagnostic procedure. Previous sections (4.2.6 and 4.3.4) have mentioned that there is no clear evidence of benefits in general from initiating antihypertensive drug treatment at SBP levels <140 mmHg (high normal BP), nor there is evidence of benefits from aiming at targets <130 mmHg. This is due to the lack of suitable studies correctly investigating these issues. Whether the presence of microvascular disease (renal, ocular, or neural) in diabetes requires treatment initiation and targets of lower BP values is also unclear. Microalbuminuria is delayed or reduced by treatment but trials in diabetic populations, including normotensives and hypertensives, have been unable to demonstrate consistently that proteinuria reduction is also accompanied by a reduction in hard CV outcomes (see also Section 6.9) [274,276,329]. No effect of antihypertensive therapy on diabetic retinopathy has been reported in normotensive and hypertensive patients in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial , and in the normotensive type-1 diabetics of the DIabetic REtinopathy Candesartan Trials (DIRECT) . Finally, antihypertensive drugs do not appear to substantially affect neuropathy . Therefore, evidence-based recommendations are to initiate antihypertensive drug treatment in all patients with diabetes whose mean SBP is >160 mmHg. Treatment is also strongly recommended in diabetic patients when SBP is >140 mmHg, with the aim to lower it consistently to <140 mmHg. As mentioned in section 184.108.40.206, DBP target between 80–85 mmHg is supported by the results of the HOT and United Kingdom Prospective Diabetes Study (UKPDS) studies [290,293]. How far below 140 mmHg the SBP target should be in patients with diabetes is not clear, since the only two large trials showing CV outcome reduction in diabetes by SBP reduction to <140 mmHg actually reduced SBP to an average of 139 mmHg [270,275]. Comparison of CV event reductions in various trials indicates that, for similar SBP differences, the benefit of more intensive lowering of SBP becomes gradually smaller when the SBP differences are in the lower part of the 139–130 mmHg range . Supportive evidence against lowering SBP <130 mmHg comes from the ACCORD trial , a post-hoc analysis of RCTs and a nationwide register-based observational study in Sweden, which suggest that benefits do not increase below 130 mmHg [326,511,512]. The case of the diabetic patient with increased urinary protein excretion is discussed in Section 6.9.
The choice of antihypertensive drugs should be based on efficacy and tolerability. All classes of antihypertensive agents are useful, according to a meta-analysis , but the individual choice should take co-morbidities into account to tailor therapy. Because BP control is more difficult in diabetes , most of the patients in all studies received combination therapy and combination therapy should most often be considered when treating diabetic hypertensives. Because of a greater effect of RAS blockers on urinary protein excretion (see Section 6.9) , it appears reasonable to have either an ACE inhibitor or an ARB in the combination. However, the simultaneous administration of two RAS blockers (including the renin inhibitor, aliskiren) should be avoided in high-risk patients because of the increased risk reported in ALTITUDE and ONTARGET [433,463]. Thiazide and thiazide-like diuretics are useful and are often used together with RAS blockers. Calcium antagonists have been shown to be useful, especially when combined with an RAS blocker. Beta-blockers, though potentially impairing insulin sensitivity, are useful for BP control in combination therapy, especially in patients with CHD and heart failure.
6.6.1 Summary of recommendations on treatment strategies in patients with diabetes
Treatment strategies in patients with diabetes
6.7 Metabolic syndrome
The metabolic syndrome is variably defined, especially because of different definitions of central obesity, although a so-called harmonized definition was presented in 2009 . Whether the metabolic syndrome is a useful clinical concept is currently disputed, largely because it has been hard to prove that it adds anything to the predictive power of individual factors [515,516]. High normal BP and hypertension constitute a frequent possible component of the metabolic syndrome , although the syndrome can also be diagnosed in the absence of a raised BP. This is consistent with the finding that hypertension, high normal BP and white-coat hypertension are often associated with increased waist circumference and insulin resistance. Co-existence of hypertension with metabolic disturbances increases global risk and the recommendation (Section 4.2.3) to prescribe antihypertensive drugs (after a suitable period of lifestyle changes) to individuals with a BP >140/90 mmHg should be implemented with particular care in hypertensive patients with metabolic disturbances. No evidence is available that BP-lowering drugs have a beneficial effect on CV outcomes in metabolic syndrome individuals with high normal BP [277,278]. As the metabolic syndrome can often be considered as a ‘prediabetic’ state, agents such as RAS blockers and calcium antagonists are preferred, since they potentially improve—or at least do not worsen—insulin sensitivity, while beta-blockers (with the exception of vasodilating beta-blockers) [407–409] and diuretics should only be considered as additional drugs, preferably at low doses. If diuretics are used, the association with a potassium-sparing agent should be considered , as there is evidence that hypokalaemia worsens glucose intolerance . Lifestyle changes, particularly weight loss and increased physical exercise, are recommended to all individuals with the metabolic syndrome. This will improve not only BP but also the metabolic components of the pattern and delay the onset of diabetes [369,519,520].
6.7.1 Summary of recommendations on treatment strategies in hypertensive patients with metabolic syndrome
Treatment strategies in hypertensive patients with metabolic syndrome
6.8 Obstructive sleep apnoea
This topic has recently been the subject of a consensus document from the ESH and the European Respiratory Society . The association between obstructive sleep apnoea and hypertension is well documented, particularly when nocturnal hypertension is concerned. Obstructive sleep apnoea appears to be responsible for a large proportion of cases of BP increase or absence of BP reduction at night-time. Although a few prospective studies have linked severe obstructive sleep apnoea to fatal and nonfatal CV events and all-cause mortality, this association appears to be closer for stroke than CHD and to be weak with obstructive sleep apnoea of mild-to-moderate severity . Whether monitoring CV and respiratory variables during night sleep should be employed systematically in individuals with resistant hypertension is open to question and no cost-effectiveness analysis has been carried out. At present, these complex methods should be preceded by ABPM showing BP abnormalities during the night or by overnight oximetry. Because of the relationship between obesity and obstructive sleep apnoea, weight loss and exercise are commonly recommended, but unfortunately no large-scale controlled trials are available . Continuous, positive airway pressure therapy is a successful procedure for reducing obstructive sleep apnoea; however, on the basis of four available meta-analyses, the effect of prolonged, continuous, positive airway pressure therapy on ambulatory BP is very small (1–2 mmHg reduction) [522–525]. This may be due to poor adherence to this complex procedure or a limited follow-up period but a recent study with a follow-up longer than 3 years has found no difference in BP or in drug usage between sleep apnoea patients who continued, or those who quitted positive air pressure therapy . However, two recent prospective studies have reported that (i) normotensive subjects with obstructive sleep apnoea were characterized over a 12-year follow-up by a significant increase in the risk of developing hypertension , and (ii) the risk of new-onset hypertension was lower in subjects treated with continuous positive air pressure , although the benefit seemed restricted to those with daytime sleepiness .
In conclusion, despite the potential health impact of obstructive sleep apnoea, well designed therapeutic studies are too few. The two more urgent issues to be investigated are whether obstructive sleep apnoea really increases the CV risk of hypertension and whether long-term therapeutic correction of obstructive sleep apnoea leads to a reduction in BP and CV events .
6.9 Diabetic and non-diabetic nephropathy
In observational studies, the relationship between BP and progression of CKD and incident ESRD is direct and progressive . Also, in the Japanese male population in general, high normal BP was associated with increased prevalence of CKD . Likewise, in a meta-analysis of intervention trials in patients with non-diabetic nephropathy, the progression of CKD correlated with achieved BP, with the slowest progression observed in patients with treated SBP in the range 110–119 mmHg . Unfortunately (see Section 220.127.116.11), these observational data are not supported by the results of three trials in which CKD patients were randomized to a lower (<125–130 mmHg) or higher (<140 mmHg) BP target [304–306]: no difference in renal failure or death was found between the two arms, except in the observational follow-up of two of these trials, in which the groups initially randomized to the lower BP had fewer cases of ESRD or death, provided that proteinuria was present [307,308,313]. In patients with diabetic or non-diabetic renal disease, SBP should be lowered to <140 mmHg and when overt proteinuria is present values <130 mmHg may be pursued, provided that changes in eGFR are monitored.
In patients with ESRD under dialysis, a recent meta-analysis showed a reduction in CV events, CV death and all-cause mortality by lowering of SBP and DBP . However, no information on the absolute BP values achieved was provided and reduction of mortality was seen in patients with heart failure only. Hence a recommendation on a precise BP target cannot be provided.
Reduction of proteinuria (both microalbuminuria and overt proteinuria) is widely considered as a therapeutic target, since observational analyses of data from RCTs have reported that changes in urinary protein excretion are predictors of adverse renal and CV events [534–536]. Once again, solid evidence is lacking from trials comparing CV or renal outcomes in groups randomized to more or less aggressive reductions of proteinuria. Several RCTs have clearly indicated that RAS blockade is more effective in reducing albuminuria than either placebo or other antihypertensive agents in diabetic nephropathy, non-diabetic nephropathy and patients with CVD [513,537], and is also effective in preventing incident microalbuminuria [329,538]. None of these trials had sufficient statistical power to evaluate effects on CV outcomes.
Achieving BP targets usually requires combination therapy and RAS blockers should be combined with other antihypertensive agents. A sub-analysis of the ACCOMPLISH trial has reported that the association of an ACE inhibitor with a calcium antagonist, rather than a thiazide diuretic, is more effective in preventing doubling serum creatinine and ESRD, though less effective in preventing proteinuria . As reported in Section 6.6, combination of two RAS blockers, though potentially more effective in reducing proteinuria, is not generally recommended [433,463]. Mineralocorticoid receptor antagonists cannot be recommended in CKD, especially in combination with an RAS blocker, because of the risk of excessive reduction in renal function and hyperkalemia . Loop diuretics should replace thiazides if serum creatinine is 1.5 mg/dL or eGFR is <30 ml/min/1.73 m2.
6.9.1 Summary of recommendations on therapeutic strategies in hypertensive patients with nephropathy
Therapeutic strategies in hypertensive patients with nephropathy
6.9.2 Chronic kidney disease stage 5D
Hypertension is a ubiquitous finding in haemodialysis patients and has major implications for survival. Detailed recommendations on how to manage high BP in patients on haemodialysis are available in guidelines issued by nephrological scientific societies and only few general considerations will be made here. Firstly, accurate measurement of BP is essential for the management of haemodialysis patients. However, a pre-haemodialysis BP may not reflect the average BP experienced by the patient. Thus, the question of how and where the measurements should be made is of particular importance, with clear evidence for the superiority of self-measured BP at home over pre-haemodialysis BP values. Secondly, the BP to be pursued by treatment in patients on haemodialysis has not been clearly established in this context. A distinct difficulty is that large alterations in sodium and water balance make BP particularly variable and that the extent of BP reductions may depend on the presence of complications such as cardiomyopathy rather that drug-induced BP control. Thirdly, all antihypertensive drugs except diuretics can be used in the haemodialysis patients, with doses determined by the haemodynamic instability and the ability of the drug to be dialysed. Drugs interfering with homeostatic adjustments to volume depletion (already severely impaired in renal insufficiency) should be avoided to minimize hypotension during the fast and intensive reduction of blood volume associated with the dialytic manoeuvres.
RCTs are rare in haemodialysis and should be encouraged. Longer or more frequent dialysis may solve the haemodynamic problems associated with salt restriction and short dialysis time .
6.10 Cerebrovascular disease
6.10.1 Acute stroke
BP management during the acute phase of stroke is a matter of continuing concern. The results of a small trial called Controlling Hypertension and Hypertension Immediately Post-Stroke (CHHIPS) suggested a beneficial impact in administering lisinopril or atenolol in patients with acute stroke and a SBP >160 mmHg . The same was the case for the Acute Candesartan Cilexetil Therapy in Stroke Survival (ACCESS) study , which suggested benefits of candesartan given for 7 days after acute stroke. This latter hypothesis was properly tested in the Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke (SCAST) trial involving more than 2000 acute stroke patients . SCAST was neutral for functional outcomes and CV endpoints, including recurrent stroke, and could not identify any subgroup with significant benefit. A recent review gives a useful update of this difficult area .
6.10.2 Previous stroke or transient ischaemic attack
Sections 4.2.6 and 18.104.22.168 have mentioned data from three major placebo-controlled RCTs of antihypertensive treatment in patients with a recent (but not acute) stroke or TIA [279,296,297], which provide somewhat conflicting evidence. No evidence is yet available that recurrent stroke is prevented by initiating therapy when BP is in the high normal range, nor is there evidence for reducing SBP to <130 mmHg.
As prevention of stroke is the most consistent benefit of antihypertensive therapy and has been observed in almost all large RCTs using different drug regimens, all regimens are acceptable for stroke prevention provided that BP is effectively reduced . Meta-analyses and meta-regression analyses suggest that calcium antagonists may have a slightly greater effectiveness on stroke prevention [284,395,421], but the two successful trials in secondary stroke prevention used a diuretic or a diuretic in combination with an ACE inhibitor [279,296]. Greater cerebrovascular protective effects have also been reported for ARBs vs. a variety of other drugs in single trials and meta-analyses [547,548].
6.10.3 Cognitive dysfunction and white matter lesions
The importance of hypertension in predicting vascular dementia has been confirmed in a recent, carefully conducted observational study in Japan , but evidence on the effects of lowering of BP is scanty and confusing. Little information was added by a cognition sub-study of HYVET in hypertensive octogenarians because of the inadequate duration of follow-up and an accompanying meta-analysis showed very limited benefit . Trials are urgently needed on preventing cognitive dysfunction and on delaying dementia when cognitive dysfunction has begun. Although white matter lesions (hyperintensities at MRI) are known to be associated with increased risk of stroke, cognitive decline and dementia (see Section 3.7.5), almost no information is available as to whether antihypertensive treatment can modify their evolution. A small sub-study of PROGRESS and a recent prospectively observational study suggest that preventing white matter hyperintensities by lowering BP is possible [551,552], but this suggestion requires verification in a large RCT.
6.10.4 Summary of recommendations on therapeutic strategies in hypertensive patients with cerebrovascular disease
Therapeutic strategies in hypertensive patients with cerebrovascular disease
6.11 Heart disease
6.11.1 Coronary heart disease
Several risk factors contribute to CHD, but the level of BP over a large and continuous range is one of the important factors, with a steeper association above a SBP of about 140 mmHg. The Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries (INTERHEART) study showed that about 50% of the population-attributable risk of a myocardial infarction can be accounted for by lipids, with hypertension accounting for about 25% . Several risk factors for CHD, and particularly SBP and DBP, are strongly related to BMI , a finding emphasizing the urgency of halting the present inexorable rise of obesity in the general population.
Sections 4.2.6 and 22.214.171.124 mentioned that RCTs of antihypertensive treatment do not provide consistent evidence that SBP target should be <130 mmHg in hypertensive patients with overt CHD, nor is there consistent evidence that antihypertensive treatment should be initiated with high normal BP. On the contrary, a number of the correlative analyses raising suspicion about the existence of a J-curve relationship between achieved BP and CV outcomes included a high proportion of CHD patients [317,318,322,323], and it is not unreasonable that, if a J-curve occurs, it may occur particularly in patients with obstructive coronary disease. The recommendation to lower SBP to <140 mmHg is indirectly strengthened by a post-hoc analysis of the INternational VErapamil SR/T Trandolapril (INVEST) study (examining all patients with CHD) showing that outcome incidence is inversely related to consistent SBP control (i.e. <140 mmHg) throughout follow-up visits .
As to which drugs are better in hypertensive patients, there is evidence for greater benefits from beta-blockers after a recent myocardial infarction , a condition in which ACE inhibitors have also been successfully tested [555,556]. Later on, all antihypertensive agents can be used . Beta-blockers and calcium antagonists are to be preferred, at least for symptomatic reasons, in cases of angina.
6.11.2 Heart failure
Hypertension is the leading attributable risk factor for developing heart failure, which is today a hypertension-related complication almost as common as stroke . Preventing heart failure is the largest benefit associated with BP-lowering drugs , including in the very elderly . This has been observed using diuretics, beta-blockers, ACE inhibitors and ARBs, with calcium antagonists apparently being less effective in comparative trials, at least in those trials in which they replaced diuretics . In ALLHAT  an ACE inhibitor was found to be less effective than a diuretic, but the study design implied initial diuretic withdrawal and the small excess of early heart failure episodes may have resulted from this withdrawal. In the Prevention Regimen for Effectively Avoiding Secondary Strokes (PROFESS) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trials [297,558], an ARB did not reduce hospitalizations for heart failure below those occurring on placebo (in which treatment consisted of non-RAS-blocking agents) and in ONTARGET . an ARB appeared (non-significantly) less effective than an ACE inhibitor.
Whilst a history of hypertension is common in patients with heart failure, a raised BP can disappear when heart failure with LV systolic dysfunction develops. No RCT has been carried out in these patients with the specific intent of testing the effects of reducing BP (in most trials of antihypertensive therapy heart failure patients have usually been excluded). In these patients evidence in favour of the administration of beta-blockers, ACE inhibitors, ARBs and mineralocorticoid receptor antagonists has been obtained from trials, in which these agents were aimed at correcting cardiac overstimulation by the sympathetic system and the RAS, rather than at lowering of BP (and indeed in a number of these trials BP changes were not reported) . In a meta-analysis of 10 prospective observational studies of heart failure patients, a higher SBP was found to be associated with better outcomes .
Hypertension is more common in heart failure patients with preserved LV ejection fraction. However, in outcome trials specifically including these patients, few had uncontrolled hypertension, probably because they received a large background therapy of BP-lowering agents. In one of these trials, Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) , the angiotensin receptor blocker irbesartan failed to lessen CV events compared with placebo. However, randomized therapy was added to optimize existing antihypertensive therapy (including 25% of ACE inhibitors) and initial BP was only 136/76 mmHg, thus further strengthening the question as to whether lowering SBP much below 140 mmHg is of any further benefit.
6.11.3 Atrial fibrillation
Hypertension is the most prevalent concomitant condition in patients with atrial fibrillation, in both Europe and the USA . Even high normal BP is associated with the development of atrial fibrillation , and hypertension is likely to be a reversible causative factor . The relationships of hypertension and antihypertensive therapy to atrial fibrillation have recently been discussed by a position paper of an ESH working group .
Hypertensive patients with atrial fibrillation should be assessed for the risk of thromboembolism by the score mentioned in the recent ESC Guidelines  and, unless contra-indications exist, the majority of them should receive oral anticoagulation therapy to prevent stroke and other embolic events [564,565]. Current therapy is based on vitamin K antagonists but newer drugs, either direct thrombin inhibitors (dabigatran) or factor Xa inhibitors (rivaroxaban,apixaban) have been shown to be non-inferior and sometimes superior to warfarin [561,563]. They are promising newcomers in this therapeutic field, although their value outside clinical trials remains to be demonstrated. In patients receiving anticoagulant therapy, good control of BP has the added advantage of reducing bleeding events .
Most patients show a high ventricular rate when in atrial fibrillation . Beta-blockers and non-dihydropyridine calcium antagonists are hence recommended as antihypertensive agents in patients with atrial fibrillation and high ventricular rate.
The consequences of atrial fibrillation include increased overall mortality, stroke, heart failure and hospitalizations; therefore prevention or retardation of new atrial fibrillation is desirable . Secondary analyses of trials in patients with LVH and hypertension have found that ARBs (losartan, valsartan) are better in preventing first occurrence of atrial fibrillation than beta-blocker (atenolol) or calcium antagonist (amlodipine) therapy, consistent with similar analyses in patients with heart failure [567–571]. This finding has not been confirmed in some more-recent trials in high-risk patients with established atherosclerotic disease, such as PRoFESS and TRANSCEND [297,558]; and irbesartan did not improve survival in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE I) trial in patients with established atrial fibrillation . ARBs have not prevented recurrences of paroxysmal or persistent atrial fibrillation [CAndesartan in the Prevention of Relapsing Atrial Fibrillation (CAPRAF) , Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation (GISSI-AF) , and ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation (ANTIPAF)  trials]. Given the heterogeneity of the available data, it has been suggested that the beneficial effects of ARBs may be limited to the prevention of incident atrial fibrillation in hypertensive patients with structural heart disease, such as LV hypertrophy or dysfunction or high risk in general, but no history of atrial fibrillation [568,576]. In patients with heart failure, beta-blockers and mineralocorticoid antagonists may also prevent atrial fibrillation [577,578]. The suggestion is indirectly supported by the results of a general practice database in the UK, with approximately 5 million patient records, reporting that ACE inhibitors and ARBs were associated with a lower risk of atrial fibrillation, compared with calcium antagonists . This has been shown also for beta-blockers in heart failure. Hence, these agents may be considered as the preferred antihypertensive agents in hypertensive patients with cardiac OD, to prevent incident atrial fibrillation.
6.11.4 Left ventricular hypertrophy
The 2009 ESH re-appraisal document summarized the evidence on why LVH, especially of the concentric type, is associated with a CVD risk higher than 20% in 10 years (i.e. high CV risk) . A number of smaller studies, but in particular the LIFE study , reported that LVH reduction is closely related to BP reduction. For similar BP reductions, ARBs, ACE inhibitors and calcium antagonists have been found, in randomized comparative studies, to be more effective than beta-blockers . In the LIFE study, which selected only hypertensive patients with LVH, the therapeutically induced reduction of LV mass was significantly associated with CV event reduction . This topic is further discussed in Section 8.4.
6.11.5 Summary of recommendations on therapeutic strategies in hypertensive patients with heart disease
Therapeutic strategies in hypertensive patients with heart disease
6.12 Atherosclerosis, arteriosclerosis, and peripheral artery disease
6.12.1 Carotid atherosclerosis
The 2007 ESH/ESC Guidelines concluded that progression of carotid atherosclerosis can be delayed by lowering BP , but calcium antagonists have a greater efficacy than diuretics and beta-blockers , and ACE inhibitors more than diuretics . Very few data are available on whether calcium antagonists have a greater effect on carotid IMT than RAS blockers.
6.12.2 Increased arterial stiffness
All antihypertensive drugs reduce arterial stiffness, since the reduction of BP unloads the stiff components of the arterial wall, leading to a passive decrease of PWV. A recent meta-analysis and meta-regression analysis of RCTs documented that ACE inhibitors and ARBs reduce PWV [582,583]. However, owing to the lack of high-quality and properly powered RTCs, it is not clear whether they are superior to other antihypertensive agents in their effect on arterial stiffness. The ability of RAS blockers to reduce arterial stiffness as assessed by PWV seems to be independent of their ability to reduce BP [582–584]. However, although the amlodipine-valsartan combination decreased central SBP more effectively than the amlodipine-atenolol combination, in the Amlodipine-Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine-Atenolol Combination (EXPLOR) trial, both combinations decreased PWV by 0.95 m/s with no significant differences over the trial 24-week duration . Also, in a randomized study in mild-to-moderate hypertension, the vasodilating beta-blocker nebivolol decreased central pulse pressure to a larger extent than the nonvasodilating beta-blocker metoprolol after 1 year of treatment, although no significant changes in the augmentation index or carotid-femoral PWV were detected with either drug . Improvement of arterial stiffness with treatment has been documented over the long term . A relationship between a reduction of arterial stiffness and reduced incidence of CV events has been reported in only one study, on a limited number of patients with advanced renal disease .
6.12.3 Peripheral artery disease
A prospective observational analysis of the UKPDS shows that the incidence of PAD-related amputation and death in patients with diabetes is strongly and inversely associated with the SBP achieved by treatment [315,587]. The choice of the antihypertensive agent is less important than actual BP control in patients with PAD . ACE inhibitors have shown benefit in a subgroup analysis of more than 4000 patients with PAD enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study , but the arm receiving the ACE inhibitor had a lower BP than the comparative arm.
There has been concern that the use of beta-blockers in patients with PAD may worsen the symptoms of claudication. Two meta-analyses of studies published in PAD patients with mild-to-moderate limb ischaemia did not confirm the intake of beta-blockers to be associated with exacerbation of PAD symptoms [589,590].
The incidence of renal artery stenosis is increased in patients with PAD. Thus, this diagnosis must be kept in mind when resistant hypertension is encountered in these patients .
6.12.4 Summary of recommendations on therapeutic strategies in hypertensive patients with atherosclerosis, arteriosclerosis, and peripheral artery disease
Therapeutic strategies in hypertensive patients with atherosclerosis, arteriosclerosis, and peripheral artery disease
6.13 Sexual dysfunction
Sexual dysfunction is more prevalent in hypertensive than normotensive individuals, but available information mostly concerns men. Erectile dysfunction is considered to be an independent CV risk factor and an early diagnostic indicator for asymptomatic or clinical OD . Hence, a full history should include sexual dysfunction. Lifestyle modifications may ameliorate erectile function . Compared with older antihypertensive drugs, newer agents (ARBs, ACE inhibitors, calcium antagonists and vasodilating beta-blockers) have neutral or even beneficial effects on erectile function . Phospho-diesterase-5 inhibitors may be safely administered to hypertensives, even those on multiple drug regimens (with the possible exception of alpha-blockers and in absence of nitrate administration)  and may improve adherence to antihypertensive therapy . Studies on the effects of hypertension and antihypertensive therapy on female sexual dysfunction are in their infancy and should be encouraged .
6.14 Resistant hypertension
Hypertension is defined as resistant to treatment when a therapeutic strategy that includes appropriate lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses (but not necessarily including a mineralocorticoid receptor antagonist) fails to lower SBP and DBP values to <140 and 90 mmHg, respectively. Depending on the population examined and the level of medical screening, the prevalence of resistant hypertension has been reported to range from 5–30% of the overall hypertensive population, with figures less than 10% probably representing the true prevalence. Resistant hypertension is associated with a high risk of CV and renal events [597–600].
Resistant hypertension can be real or only apparent or spurious. A frequent cause of spurious resistant hypertension is failure to adhere to the prescribed treatment regimen, a notoriously common phenomenon that is responsible for the poor rate of BP control in the hypertensive population worldwide. Lack of BP control may, however, also depend on (i) persistence of an alerting reaction to the BP-measuring procedure, with an elevation of office (although not of out-of-office) BP (ii) use of small cuffs on large arms, with inadequate compression of the vessel and (iii) pseudohypertension, i.e. marked arterial stiffening (more common in the elderly, especially with heavily calcified arteries), which prevents occlusion of the brachial artery.
True resistant hypertension may originate from: (i) lifestyle factors such as obesity or large weight gains, excessive alcohol consumption (even in the form of binge drinking) and high sodium intake, which may oppose the BP-lowering effect of antihypertensive drugs via systemic vasoconstriction, sodium and water retention and, for obesity, the sympatho-stimulating effect of insulin resistance and increased insulin levels; (ii) chronic intake of vasopressor or sodium-retaining substances; (iii) obstructive sleep apnoea (usually but not invariably associated with obesity) , possibly because nocturnal hypoxia, chemoreceptor stimulation and sleep deprivation may have a long-lasting vasoconstrictor effect; (iv) undetected secondary forms of hypertension and (v) advanced and irreversible OD, particularly when it involves renal function or leads to a marked increase in arteriolar wall-lumen ratio or reduction of large artery distensibility.
A correct diagnostic approach to resistant hypertension requires detailed information on the patient's history (including lifestyle characteristics), a meticulous physical examination and laboratory tests to detect associated risk factors, OD and alterations of glucose metabolism, as well as of advanced renal dysfunction opposing—via sodium retention—the effect of BP-lowering drugs. The possibility of a secondary cause of hypertension should always be considered: primary aldosteronism may be more frequent than was believed years ago , and renal artery stenoses of an atherosclerotic nature have been shown to be quite common in the elderly. Finally, ABPM should be performed regularly, not only to exclude spurious resistance but also to quantify to a better degree the BP elevation and the subsequent effect of the treatment modifications [598,602].
In clinical practice, identification of low adherence to treatment may present special difficulties, because (i) information provided by the patient may be misleading and (ii) methods to objectively measure adherence to treatment have little applicability in day-to-day medicine. An unhealthy lifestyle may represent a clue, as may a patient's expression of negative feelings about medicines in general. Ultimately, physicians may have to consider stopping all current drugs and restart with a simpler treatment regimen under close medical supervision. This approach may also avoid futile use of ineffective drugs. Although hospitalization for hypertension is regarded as inappropriate in most European countries, a few days in hospital may be necessary to check the BP effect of antihypertensive drugs under strict control.
Although resistant hypertension may show a BP reduction if the diuretic dose is further increased (see below), most patients with this condition require the administration of more than three drugs. Subgroup analyses of large-scale trials and observational studies have provided evidence that all drug classes with mechanisms of action partially or totally different from those of the existing three drug regimens can lower BP in at least some resistant hypertensive individuals . A good response has been reported to the use of mineralocorticoid receptor antagonists, i.e. spironolactone, even at low doses (25–50 mg/day) or eplerenone, the alpha-1-blocker doxazosin and a further increase in diuretic dose [604–608], loop diuretic replacing thiazides or chlorthalidone if renal function is impaired. Given that blood volume may be elevated in refractory hypertension , amiloride may add its effect to that of a previously administered thiazide or thiazide-like diuretic, although its use may favour hyperkalaemia and is not indicated in patients with marked reduction of eGFR. The BP response to spironolactone or eplerenone may be accounted for by the elevated plasma aldosterone levels frequently accompanying resistant hypertension, either because aldosterone secretion escapes the early reduction associated with RAS blockade  or because of undetected primary aldosteronism.
At variance from an earlier report , endothelin antagonists have not been found to effectively reduce clinic BP in resistant hypertension and their use has also been associated with a considerable rate of side-effects . New BP-lowering drugs (nitric oxide donors, vasopressin antagonists, neutral endopeptidase inhibitors, aldosterone synthase inhibitors, etc.) are all undergoing early stages of investigation . No other novel approach to drug treatment of resistant hypertensive patients is currently available.
6.14.1 Carotid baroreceptor stimulation
Chronic field electrical stimulation of carotid sinus nerves via implanted devices has recently been reported to reduce SBP and DBP in resistant hypertensive individuals [614–616]. The reduction was quite marked when initial BP values were very high and the effect included ambulatory BP and persisted for up to 53 months . However, longer-term observations have so far involved only a restricted number of patients and further data on larger numbers of individuals with an elevation of BP unresponsive to multiple drug treatments are necessary to confirm the persistent efficacy of the procedure. Although only a few remediable side-effects of a local nature (infection, nerve damage, pain of glossopharyngeal nerve origin, etc) have so far been reported, a larger database is also needed to conclusively establish its safety. Ongoing technical improvements to reduce the inconvenience represented by the surgical implantation of the stimulating devices, and to prolong the duration of the battery providing the stimulation, are being tested.
6.14.2 Renal denervation
A growing non-drug therapeutic approach to resistant hypertension is bilateral destruction of the renal nerves travelling along the renal artery, by radiofrequency ablation catheters of various design, percutaneously inserted through the femoral artery [617–621]. The rationale for renal denervation lays in the importance of sympathetic influences on renal vascular resistance, renin release and sodium re-absorption, the increased sympathetic tone to the kidney and other organs displayed by hypertensive patients [622–624], and the pressor effect of renal afferent fibres, documented in experimental animals [625,626]. The procedure has been shown to induce a marked reduction in office BP which has been found to be sustained after one year and in a small number of patients two and three years following the denervation procedure. Limited reductions have been observed on ambulatory and home BP, and need of antihypertensive drugs , while some evidence of additional benefit, such as decrease of arterial stiffening, reversal of LVH and diastolic dysfunction, renal protection and improvement of glucose tolerance, has been obtained [628–630]. Except for the rare problems related to the catheterization procedure (local haematoma, vessel dissection, etc) no major complications or deterioration of renal function have been reported.
At present, the renal denervation method is promising, but in need of additional data from properly designed long-term comparison trials to conclusively establish its safety and persistent efficacy vs. the best possible drug treatments. Understanding what makes renal denervation effective or ineffective (patient characteristics or failure to achieve renal sympathectomy) will also be important to avoid the procedure in individuals unlikely to respond. A position paper of the ESH on renal denervation should be consulted for more details .
6.14.3 Other invasive approaches
Research in this area is ongoing and new invasive procedures are under study. Examples are creation of a venous-arterial fistula and neurovascular decompression by surgical interventions, which has been found to lower BP in a few cases of severe resistant hypertension (presumably by reducing central sympathetic overactivity) with, however, an attenuation of the effect after 2 years . New catheters are also available to shorten the renal ablation procedure and to achieve renal denervation by means other than radiofrequency, e.g. by ultrasounds.
Overall, renal denervation and carotid baroreceptor stimulation should be restricted to resistant hypertensive patients at particularly high risk, after fully documenting the inefficacy of additional antihypertensive drugs to achieve BP control. For either approach, it will be of fundamental importance to determine whether the BP reductions are accompanied by a reduced incidence of CV morbid and fatal events, given the recent evidence from the FEVER and Valsartan Antihypertensive Long-term Use Evaluation (VALUE) studies that, in patients under multidrug treatment, CV risk (i) was greater than in patients on initial randomized monotherapy and (ii) did not decrease as a result of a fall in BP [633,634]. This raises the possibility of risk irreversibility, which should be properly studied.
6.14.4 Follow-up in resistant hypertension
Patients with resistant hypertension should be monitored closely. Office BP should be measured at frequent intervals and ambulatory BP at least once a year. Frequent home BP measures can also be considered and measures of organ structure and function (particularly of the kidney) instituted on a yearly basis. Although mineralocorticoid receptor antagonists at low doses have been associated with relatively few side-effects, their use should prompt frequent assessment of serum potassium and serum creatinine concentrations, because these patients may undergo acutely or chronically an impairment of renal function, especially if there is concomitant treatment with an RAS blocker. Until more evidence is available on the long-term efficacy and safety of renal denervation and baroreceptor stimulation, implementation of these procedures should be restricted to experienced operators, and diagnosis and follow-up restricted to hypertension centres .
6.14.5 Summary of recommendations on therapeutic strategies in patients with resistant hypertension
Therapeutic strategies in patients with resistant hypertension
6.15 Malignant hypertension
Malignant hypertension is a hypertensive emergency, clinically defined as the presence of very high BP associated with ischaemic OD (retina, kidney, heart or brain). Although its frequency is very low, the absolute number of new cases has not changed much over the past 40 years. The survival rate 5 years after diagnosis of malignant hypertension has improved significantly (it was close to zero 50 years ago), possibly as a result of earlier diagnosis, lower BP targets and availability of new classes of antihypertensive agents . OD may regress—at least partially— under treatment , although long-term prognosis remains poor, especially when renal function is severely reduced . Because of its low incidence, no good controlled study has been conducted with recent agents. Current treatment is founded on agents that can be administered by intravenous infusion and titrated, and so can act promptly but gradually in order to avoid excessive hypotension and further ischaemic OD. Labetalol, sodium nitroprusside, nicardipine, nitrates and furosemide are among the intravenous agents most usually employed but in these severely ill patients, treatment should be individualized by the physician. When diuretics are insufficient to correct volume retention, ultrafiltration and temporary dialysis may help.
6.16 Hypertensive emergencies and urgencies
Hypertensive emergencies are defined as large elevations in SBP or DBP (>180 mmHg or >120 mmHg, respectively) associated with impending or progressive OD, such as major neurological changes, hypertensive encephalopathy, cerebral infarction, intracranial haemorrhage, acute LV failure, acute pulmonary oedema, aortic dissection, renal failure, or eclampsia. Isolated large BP elevations without acute OD (hypertensive urgencies)—often associated with treatment discontinuation or reduction as well as with anxiety—should not be considered an emergency but treated by reinstitution or intensification of drug therapy and treatment of anxiety. Suspicions have recently been raised on the possible damaging effect of maximum vs. predominant BP values . However, this requires more information and overtreatment should be avoided.
Treatment of hypertensive emergencies depends on the type of associated OD and ranges from no lowering, or extremely cautious lowering, of BP in acute stroke (see Section 6.10) to prompt and aggressive BP reduction in acute pulmonary oedema or aortic dissection. In most other cases, it is suggested that physicians induce a prompt but partial BP decrease, aiming at a <25% BP reduction during the first hours, and proceed cautiously thereafter. Drugs to be used, initially intravenously and subsequently orally, are those recommended for malignant hypertension (see Section 6.15). All suggestions in this area, except those for acute stroke, are based on experience because of the lack of any RCTs comparing aggressive vs. conservative lowering of BP, and the decision on how to proceed should be individualized.
6.17 Perioperative management of hypertension
Presence of hypertension is one of the common reasons for postponing necessary surgery, but it is arguable whether this is necessary . Stratifying the overall CV risk of the surgery candidate may be more important . The question of whether antihypertensive therapy should be maintained immediately before surgery is frequently debated. Sudden withdrawal of clonidine or beta-blockers should be avoided because of potential BP or heart-rate rebounds. Both types of agent can be continued over surgery and, when patients are unable to take oral medications, beta-blockers can be given parenterally and clonidine transdermally. Diuretics should be avoided on the day of surgery because of potential adverse interaction with surgery-dependent fluid depletion. ACE inhibitors and ARBs may also be potentiated by surgery-dependent fluid depletion and it has been suggested that they should not be taken on the day of surgery and restarted after fluid repletion has been assured. Post-surgery BP elevation, when it occurs, is frequently caused by anxiety and pain after awakening, and disappears after treating anxiety and pain. All these suggestions are based on experience only (Class IIb, Level C).
6.18 Renovascular hypertension
Renovascular artery stenosis secondary to atherosclerosis is relatively frequent, especially in the elderly population, but rarely progresses to hypertension or renal insufficiency . It is still debated whether patients with hypertension or renal insufficiency benefit from interventions: mostly percutaneous renal artery stenting. While there is convincing (though uncontrolled) information favouring this procedure in younger (mostly female) patients with uncontrolled hypertension in fibromuscular hyperplasia (82–100% success, re-stenosis in 10–11%)  (Class IIa, Level B), the matter is highly controversial in atherosclerotic renovascular hypertension. Two retrospective studies have reported improvements (though not in mortality) in patients with bilateral renal artery stenosis complicated by recurrent episodes of acute heart failure . In all other conditions with renal artery stenosis, uncertainties continue regarding the benefit of angioplasty and stenting, despite several controlled trials. Two RCTs and 21 cohort studies published before 2007 showed no uniform pattern of benefit. The more recent Angioplasty and STenting for Renal Artery Lesions (ASTRAL) trial, including 806 patients randomized between angioplasty and stenting, plus medical therapy vs. medical therapy alone, did not provide any evidence of clinically meaningful benefit on BP, renal function, or CV events . Although no final conclusions can be drawn from ASTRAL because of some limitations in its design (patients with a strong indication for intervention were excluded from randomization) and lack of statistical power, intervention is at present not recommended in atherosclerotic renal artery stenosis if renal function has remained stable over the past 6–12 months and if hypertension can be controlled by an acceptable medical regimen (Class ill, Level B). Suitable medical regimens can include RAS blockers, except in bilateral renal artery stenosis or in unilateral artery stenosis with evidence of functional importance by ultrasound examinations or scintigraphy.
6.19 Primary aldosteronism
In documented unilateral primary aldosteronism, caused either by aldosterone-producing adenoma or unilateral adrenal hyperplasia, the treatment of choice is unilateral laparoscopic adrenalectomy, whereas treatment with mineralocorticoid receptor antagonists is indicated in patients with bilateral adrenal disease (idiopathic adrenal hyperplasia and bilateral adenoma). Glucocorticoid-remediable aldosteronism is treated with a low dose of a long-acting glucocorticoid, e.g. dexamethasone.
Surgical treatment in patients with unilateral primary aldosteronism shows improvement of postoperative serum potassium concentrations in nearly 100% of patients , when diagnosis of—and indication for—adrenalectomy are based on adrenal venous sampling. Hypertension is cured (defined as BP <140/90 mmHg without antihypertensive medication) in about 50% (range: 35–60%) of patients with primary aldosteronism after unilateral adrenalectomy. Cure is more likely in patients having no more than one first-degree relative with hypertension, preoperative use of two antihypertensive drugs at most, younger age, shorter duration of hypertension and no vascular remodelling [645,646].
Mineralocorticoid receptor antagonists (spironolactone, eplerenone) are indicated in patients presenting with bilateral adrenal disease and in those who, for various reasons, do not undergo surgery for unilateral primary aldosteronism. The starting dose for spironolactone should be 12.5–25 mg daily in a single dose; the lowest effective dose should be found, very gradually titrating upwards to a dose of 100 mg daily or more. The incidence of gynaecomasty with spironolactone is dose-related whereas the exact incidence of menstrual disturbances in premenopausal women with spironolactone is unknown. A small dose of a thiazide diuretic, triamterene or amiloride, can be added to avoid a higher dose of spironolactone, which may cause side-effects.
Eplerenone is a newer, selective mineralocorticoid receptor antagonist without antiandrogen and progesterone agonist effects, thus reducing the rate of side-effects; it has 60% of the antagonist potency of spironolactone. Because of its shorter duration of action, multiple daily dosing is required (with a starting dose of 25 mg twice daily). In a recent 16-week, double-blind, randomized study comparing the antihypertensive effect of eplerenone (100–300 mg once daily) and spironolactone (75–225 mg once daily), spironolactone was significantly superior to eplerenone in reducing BP in primary aldosteronism .
7. TREATMENT OF ASSOCIATED RISK FACTORS
7.1 Lipid-lowering agents
Patients with hypertension, and especially those with type 2 diabetes or metabolic syndrome, often have atherogenic dyslipidemia, characterized by elevated triglycerides and LDL-cholesterol with a low HDL-cholesterol [12,13,648]. The benefit of adding a statin to antihypertensive treatment was well established by the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) study , as summarized in the 2007 ESH/ESC Guidelines . The lack of statistically significant benefit in the ALLHAT study can be attributed to insufficient lowering of total cholesterol (11% in ALLHAT, compared with 20% in ASCOT) . Further analyses of the ASCOT data have shown that the addition of a statin to the amlodipine-based antihypertensive therapy can reduce the incidence of the primary CV outcome even more markedly than the addition of a statin to the atenolol-based therapy . The beneficial effect of statin administration to patients without previous CV events [targeting a low-density lipoprotein cholesterol value <3.0 mmol/L; (115 mg/dL)] has been strengthened by the findings of the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study , showing that lowering low-density lipoprotein cholesterol by 50% in patients with baseline values <3.4 mmol/L (130 mg/dL) but with elevated C-reactive protein reduced CV events by 44%. This justifies use of statins in hypertensive patients who have a high CV risk.
As detailed in the recent ESC/EAS Guidelines , when overt CHD is present, there is clear evidence that statins should be administered to achieve low-density lipoprotein cholesterol levels <1.8 mmol/L (70 mg/dL) . Beneficial effects of statin therapy have also been shown in patients with a previous stroke, with low-density lipoprotein cholesterol targets definitely lower than 3.5 mmol/L (135 mg/dL) . Whether they also benefit from a target <1.8 mmol/L (70 mg/dL) is open to future research. This is the case also for hypertensive patients with a low- moderate CV risk, in whom evidence of the beneficial effects of statin administration is not clear .
7.2 Antiplatelet therapy
In secondary CV prevention, a large meta-analysis published in 2009 showed that aspirin administration yielded an absolute reduction in CV outcomes much larger than the absolute excess of major bleedings . In primary prevention, however, the relationship between benefit and harm is different, as the absolute CV event reduction is small and only slightly greater than the absolute excess in major bleedings. A more favourable balance between benefit and harm of aspirin administration has been investigated in special groups of primary prevention patients. Studies on diabetes have so far failed to establish a favourable benefit-harm ratio, whereas a sub-study of the HOT trial, in which hypertensive patients were classified on the basis of eGFR at randomization, showed aspirin administration to be associated with a significant trend for a progressive reduction in major CV events and death, the lower the baseline eGFR values. This reduction was particularly marked in hypertensive patients with eGFR <45 mL/min/1.73 m2. In this group of patients the risk of bleeding was modest compared with the CV benefit . Aspirin therapy should be given only when BP is well controlled.
In conclusion, the prudent recommendations of the 2007 ESH/ESC Guidelines can be reconfirmed : antiplatelet therapy, particularly low-dose aspirin, should be prescribed to controlled hypertensive patients with previous CV events and considered in hypertensive patients with reduced renal function or a high CV risk. Aspirin is not recommended in low-to-moderate risk hypertensive patients in whom absolute benefit and harm are equivalent. It is noteworthy that a recent meta-analysis has shown lower incidences of cancer and mortality in the aspirin (but not the warfarin) arm of primary prevention trials . If confirmed, this additional action of aspirin may lead to a more liberal reconsideration of its use. Low-dose aspirin in the prevention of preeclampsia is discussed in Section 6.5.3.
7.3 Treatment of hyperglycaemia
The treatment of hyperglycaemia for prevention of CV complications in patients with diabetes has been evaluated in a number of studies. For patients with type 1 diabetes, the Diabetes Control and Complications (DCCT) study convincingly showed that intensive insulin therapy was superior for vascular protection and reduction of events, compared with standard treatment [660,661]. In type 2 diabetes, several large-scale studies have aimed at investigating whether a tight glycaemic control, based on oral drugs and/or insulin, is superior to less-tight control for CV prevention. In UKPDS, tighter glycaemic control could prevent microvascular—but not macrovascular—complications , except in a subgroup with obesity, treated with metformin . The appropriate target for a glycaemic control has been explored recently in the ADVANCE , ACCORD , and Veterans’ Affairs Diabetes Trial (VADT)  studies, which randomized one study arm to very low HbA1c targets (<6.5 or 6.0%). None of these individual studies showed a significant reduction of the composite endpoint of combined CVD events, but a number of later meta-analyses have documented that more intensive glycaemic control is likely to reduce non-fatal coronary events and myocardial infarction, as well as nephropathy, but not stroke or all-cause or CV mortality [667–669]. However, especially in ACCORD, the lower HbA1c target arm was associated with an excess of hypoglycaemic episodes and all-cause mortality. Based on these data, the American Diabetology Association and the European Association for the Study of Diabetes (EASD)  have jointly taken a similar, prudent attitude, recommending that physicians individualize treatment targets and avoid overtreatment of fragile, higher-risk patients by restricting more stringent control of hyperglycaemia to younger patients with recent diabetes, absent or minor vascular complications and long life-expectancy (HbA1c target <7.0%), while considering a less-stringent HbA1c of 7.5–8.0%, or even higher in more complicated and fragile patients, particularly in elderly patients with cognitive problems and a limited capacity for self care [670,671]. The ESC/EASD Guidelines for the treatment of diabetes should be consulted for more details .
7.4 Summary of recommendations on treatment of risk factors associated with hypertension
Treatment of risk factors associated with hypertension
8.1 Follow-up of hypertensive patients
After the initiation of antihypertensive drug therapy, it is important to see the patient at 2- to 4-week intervals to evaluate the effects on BP and to assess possible side-effects. Some medications will have an effect within days or weeks but a continued delayed response may occur during the first 2 months. Once the target is reached, a visit interval of a few months is reasonable, and evidence has been obtained that no difference exists in BP control between 3- and 6-month intervals . Depending on the local organization of health resources, many of the later visits may be performed by non-physician health workers, such as nurses . For stable patients, HBPM and electronic communication with the physician (SMS, E-mail, social media, or automated telecommunication of home BP readings) may also provide an acceptable alternative [675–677]. It is nevertheless advisable to assess risk factors and asymptomatic OD at least every 2 years.
8.2 Follow-up of subjects with high normal blood pressure and white-coat hypertension
Individuals with high normal BP or white-coat hypertension frequently have additional risk factors, including asymptomatic OD, with a higher chance of developing office or sustained hypertension, respectively [285,351,678–681] (see Section 3.1.3). Even if untreated, they should be scheduled for regular follow-up (at least annual visits) to measure office and out-of-office BP as well as to check the CV risk profile. Regular annual visits should also serve the purpose of reinforcing recommendations on lifestyle changes, which represent the appropriate treatment in many of these patients.
8.3 Elevated blood pressure at control visits
Patients and physicians have a tendency to interpret an uncontrolled BP at a given visit as due to occasional factors and thus to downplay its clinical significance. This should be avoided and the finding of an elevated BP should always lead physicians to search for the cause(s), particularly the most common ones, such as poor adherence to the prescribed treatment regimen, persistence of a white-coat effect and occasional or more-regular consumption of drugs or substances that raise BP or oppose the antihypertensive effect of treatment (e.g. alcohol, nonsteroidal anti-inflammatory drugs). This may require tactful but stringent questioning of the patient (and his/her relatives), as well as repeated measurements of BP, to attenuate the initial alerting response to the BP-measuring procedures. If ineffective treatment is regarded as the reason for inadequate BP control, the treatment regimen should be modified without delay to avoid clinical inertia—major contribution to poor BP control worldwide [682,683]. Consideration should be given to the evidence that visit-to-visit BP variability may be a determinant of CV risk, independently of the mean BP levels achieved during long-term treatment, and that, thus, CV protection may be greater in patients with consistent BP control throughout visits.
8.4 Continued search for asymptomatic organ damage
Several studies have shown that the regression of asymptomatic OD occurring during treatment reflects the treatment-induced reduction of morbid and fatal CV events, thereby offering valuable information on whether patients are more or less effectively protected by the treatment strategies adopted. This has been shown for the treatment-induced regression of electrocardiographic LVH (voltage or strain criteria), the echocardiographic LVH and the echocardiographically derived measures of LVM and left atrial size [150,151,261,684–686]. Lower incidence of CV events and slower progression of renal disease have also been repeatedly associated with treatment-induced reduction in urinary protein excretion in both diabetic and nondiabetic patients [227,262,535,536,687,688] but, especially for microalbuminuria, discordant results have also been reported [329,331]. This has also been the case in a recent sub-analysis of the ACCOMPLISH trial, in which the combination of an ACE inhibitor and a calcium antagonist was more effective than an ACE inhibitor-diuretic combination in preventing the doubling of serum creatinine or ESRD while reducing proteinuria to a lesser degree . A recent analysis of the ELSA study has, on the other hand, failed to consistently document a predictive value for CV events of treatment-induced reductions in carotid IMT (possibly because the changes are minimal and their impact masked by large between-subject differences) . This conclusion is supported by meta-analyses [689–691], though some of them have been discussed . Evidence on the predictive power of treatment-induced changes in other measures of OD (eGFR, PWV and ABI) is either limited or absent. On the whole, it appears reasonable to search for at least some asymptomatic OD, not only for the initial stratification of CV risk, but also during follow-up.
A cost-effectiveness analysis of which signs of OD should best be assessed in the follow-up of hypertensive patients has never been done. Assessment of urinary protein excretion can be reliably quantified in a morning urine sample and has a low cost, wide availability and ability to show a treatment-induced effect within a few months. Also, the low cost and wide availability suggest regular repetition of an electrocardiogram, although detection of its LVH-dependent change is less sensitive. Treatment-induced changes are also slow for echocardiographic measures of LVM, which also carries the disadvantage of reduced availability, higher cost, extra-time and need of refined expertise for proper assessment. The information available on assessment of OD during antihypertensive treatment is summarized in Fig. 5. In addition, follow-up measurements should include lipid profile, blood glucose, serum creatinine and serum potassium and, regardless of their greater or smaller ability to accurately and quickly detect regression with treatment, all measures of OD may provide useful information on the progression of hypertension-dependent abnormalities, as well as on the appearance of conditions requiring additional therapeutic interventions, such as arrhythmias, myocardial ischaemia, stenotic plaques and heart failure.
8.5 Can antihypertensive medications be reduced or stopped?
In some patients, in whom treatment is accompanied by an effective BP control for an extended period, it may be possible to reduce the number and dosage of drugs. This may be particularly the case if BP control is accompanied by healthy lifestyle changes, such as weight loss, exercise habits and a low-fat and low-salt diet, which remove environmental pressor influences. Reduction of medications should be made gradually and the patient should frequently be checked because of the risk of reappearance of hypertension.
9. IMPROVEMENT OF BLOOD PRESSURE CONTROL IN HYPERTENSION
Despite overwhelming evidence that hypertension is a major CV risk factor and that BP-lowering strategies substantially reduce the risk, studies performed outside Europe and in several European countries [16,683] consistently show that (i) a noticeable proportion of hypertensive individuals are unaware of this condition or, if aware, do not undergo treatment [693,694], (ii) target BP levels are seldom achieved, regardless of whether treatment is prescribed or patients are followed by specialists or general practitioners [695,696] (iii), failure to achieve BP control is associated with persistence of an elevated CV risk, [697,698] and (iv) the rate of awareness of hypertension and BP control is improving slowly or not at all—and this is the case also in secondary prevention [699,700]. Because, in clinical trials, antihypertensive treatment can achieve BP control in the majority of the patients , these data reflect the wide gap that exists between the antihypertensive treatment potential and real-life practice. As a consequence, high BP remains a leading cause of death and CV morbidity in Europe, as elsewhere in the world . Thus there is a strong need to detect and treat more hypertensive patients, as well as improve the efficacy of ongoing treatment.
Overall, three main causes of the low rate of BP control in real life have been identified: (i) physician inertia ; (ii) patient low adherence to treatment [704,705], and (iii) deficiencies of healthcare systems in their approach to chronic diseases. However, delayed initiation of treatment when OD is irreversible or scarcely reversible is also likely to be an important factor . Physician inertia (i.e. lack of therapeutic action when the patient's BP is uncontrolled) is generated by several factors: doubts about the risk represented by high BP (particularly in the elderly), fear of a reduction in vital organ perfusion when BP is reduced (the J-curve phenomenon) and concern about side-effects. Several physicians also maintain a sceptical attitude towards guidelines because of their multiplicity and origin from different sources (international and national scientific societies, governmental agencies, local hospitals, etc.), which make their recommendations sometimes inconsistent. Recommendations are also often perceived as unrealistic when applied to the environment where physicians operate .
Low adherence to treatment is an even more important cause of poor BP control because it involves a large number of patients and its relationship with persistence of elevated BP values and high CV risk has been fully documented [704–710]. Non-adherence has been classified into ‘discontinuers’ (patients who discontinue treatment) and ‘bad users’ [i.e. those who take treatment irregularly because of delays in drug(s) intake or repeated short interruptions of the prescribed therapeutic strategy]. Discontinuers represent a greater problem because their behaviour is normally intentional and, once discontinued, treatment resumption is more difficult. Bad users, however, are at higher risk of becoming discontinuers, and thus their identification is important.
Low adherence is extremely common for lifestyle changes but importantly extends to drug prescriptions, for which it develops quite rapidly: after 6 months, more than one-third and after 1 year about half of the patients may stop their initial treatment; furthermore, on a daily basis, 10% of patients forget to take their drug [704,705]. For hypertension (and other chronic diseases), investigating adherence to treatment is now facilitated by electronic methods of measuring adherence and by the availability of administrative databases that provide information for the entire population [709,711].
Several approaches have been proposed to reduce physician inertia, unawareness of hypertension and nonadherence to treatment. Physician training programmes notably reduce inertia although perhaps with less than expected benefits [712–714], and there is consensus that making simple, informative material available in the lay press, the physician's office, pharmacies, schools and other public places may have a favourable effect on information and motivation by interested individuals . Emphasis should be placed on the importance of measuring and reporting BP values, even at visits not connected with hypertension or problems of a CV nature, in order to collate information on BP status over the years. Adherence to treatment can also be improved by simplification of treatment  and use of self-measured BP at home ; an additional favourable effect might be gained through the use of telemetry for transmission of recorded home values [98,99].
Health providers should facilitate guidelines implementation as a means of educating physicians about recent scientific data, rather than primarily as an instrument to contain cost. They should also foster a multidisciplinary approach to CV prevention, which could mean that physicians receive the same motivating message from different perspectives. The most serious attempt by a healthcare system to improve the diagnostic and treatment aspects of hypertension has been done in the UK, based on the pay-per-performance principle, i.e. to give incentives to physicians rewarding the appropriate diagnosis and care of chronic diseases, including hypertension. The impact on the quality and outcomes of care for hypertension is uncertain. An early report showed that the implementation was associated with an increased rate of BP monitoring and control among general practitioners , whereas later reports showed that the trend was not sustained. Furthermore, no statistically significant changes in the cumulative incidence of major hypertension-related adverse outcomes or mortality have been observed after implementation of pay-for-performance for the subgroups of already treated and newly treated patients [718,719].
A list of the interventions associated with improved patient adherence to treatment in shown in Table 17.
10. HYPERTENSION DISEASE MANAGEMENT
While there is strong evidence that antihypertensive treatment has a protective effect (see Section 4.1), it is less clear how care for hypertensive patients should be organized and delivered in the community . However, there seems to be little doubt that, for effective disease management, a multidisciplinary approach is required. This means the involvement of a variety of healthcare providers [720–722]: the general practitioner, who should take care of the majority of hypertensive patients; medical specialists from various fields depending on the nature of the hypertension and the difficulty posed by its treatment; specifically trained nurses to closely follow the patient during his or her lifetime treatment; and pharmacists who handle physicians’ prescriptions and often have to deal directly with the patients’ problems and reply to his or her questions. In an ideal setting, all healthcare providers should co-operate in a successful lifetime intervention against this condition. In a review of the results of 13 studies, interpretation of disease management programmes resulted in a significantly greater SBP and DBP reduction, compared with controls. The effect was equivalent to an about 5 mmHg and >4 mmHg greater effect on SBP and DBP, respectively .
10.1 Team approach in disease management
Wide variations exist in the organization of healthcare systems across Europe but, in most countries, hypertension is usually diagnosed and managed in primary care (i.e. by general practitioners). In some countries, practice-based specialists take care of more complex examinations (ultrasounds etc.) and the more difficult-to-treat cases, while in other countries only hospital-based specialists and hypertension units are available for referral. In a few countries, specially educated and trained nurses assist physicians in the prescription, consultation, referral and even hospital admission of individuals with raised BP. In most countries, however, nurses have little or no role-sharing with physicians.
Several studies are available to show that team-based care can reduce BP by several mmHg more than standard care , with a greater SBP reduction of about 10 mmHg (median value) and an approximately 22% greater rate of BP control in a meta-analysis from 37 comparisons between team-based and standard-treatment groups . Compared with standard care, team-based care has been found to be effective if it involves nurses and/or pharmacists either within a clinic or in the community . The beneficial effect of the involvement of pharmacists and nurses in the management of hypertension has been obtained when their task involved patient education, behavioural and medical counselling, assessment of adherence to treatment, and, for pharmacists, interaction with physicians in the area of guideline-based therapy [724,726,727]. In a review of 33 RCTs published between 2005 and 2009, BP targets were more commonly achieved when interactions included a step-care treatment algorithm administered by nurses, as well as the involvement of nurses in patient monitoring by telephone [726,728,729]. Clearly, team-based strategies offer an important potential method for improvement of antihypertensive treatment compared with strategies involving physicians alone. Physicians, nurses and pharmacists should all be represented and general practitioners should interact, when needed, with specialists from various areas, such as internists, cardiologists, nephrologists, endocrinologists and dieticians. The contribution of nurses may be particularly important for implementation of lifestyle changes, for which long-term adherence is, notoriously, extremely low. Details on how team work for hypertension management may be organized are available in a recent publication on ESH Excellence Centres .
10.2 Mode of care delivery
Care is normally delivered on a face-to-face basis i.e. during an office visit in the primary care setting, in a specialist's office, or in hospital. Other methods for the delivery of care are, however, available, such as telephone interviews and advanced telemedicine (including videoconferences). Telephone contacts are effective in changing patient behaviours, with the additional potential advantage that, compared with face-to-face contact  (i) more patients can be reached, (ii) little or no time or working hours are lost, and (iii) contacts can be more frequent, with a greater chance of addressing patients’ concerns in a timely manner, tailoring treatment and ultimately improving adherence. It is nevertheless important to emphasize that these new models of care delivery do not represent a substitute for office visits, but rather offer a potentially useful addition to the strategy of establishing a good relationship between the patient and the healthcare providers.
10.3 The role of information and communication technologies
Studies using communication technologies have shown that there are many new ways by which healthcare teams can communicate with patients, with the theoretical advantage of timely and effective adjustment of care plans. Home BP telemonitoring represents an appropriate example: several studies have shown that electronic transmission of self-measured BP can lead to better adherence to treatment regimen and more effective BP control [677,728,731,732]. Other examples include the use of smart phones, cell phones, Bluetooth, texting, personal electronic health records and patient portals, all aimed at favouring self-monitoring of treatment efficacy, adherence to prescription and feedback to healthcare personnel. It should be noted, however, that for no such device has effectiveness been proven in an RCT; thus their advantage over classical medical approaches remains to be established [723,724,731–734].
The impact of information and communication technologies in general, and of computerized decision-support systems in particular, on patient risk management and safety is analysed in detail in the e-Health for Safety report published by the European Commission in 2007 (review.epractice-en/en/library/302671). The report maintains that these systems can (i) prevent medical errors and adverse events, (ii) initiate rapid responses to an event, enable its tracking and provide feedback to learn from, (iii) provide information that can ease diagnostic and therapeutic decisions, and (iv) favour involvement of the patient in the decision-making process with an advantage to his or her co-operation and adherence .
Connecting the patient's health records to a variety of electronic health records (from different providers, pharmacies, laboratories, hospitals, or insurers) may foster the development of tailored tools for the individual patient, enhancing his or her engagement in care and disease prevention and improving health outcomes and patient satisfaction. Further developments are the incorporation of computerized technology that may help in the decision-making process to manage high BP.
11. GAPS IN EVIDENCE AND NEED FOR FUTURE TRIALS
Based on the review of the evidence available for the 2013 Guidelines on hypertension, it is apparent that several therapeutic issues are still open to question and would benefit from further investigation:
1. Should antihypertensive drug treatment be given to all patients with grade 1 hypertension when their CV risk is low-to-moderate?
2. Should elderly patients with a SBP between 140 and 160 mmHg be given antihypertensive drug treatments?
3. Should drug treatment be given to subjects with white-coat hypertension? Can this condition be differentiated into patients needing or not needing treatment?
4. Should antihypertensive drug treatment be started in the high normal BP range and, if so, in which patients?
5. What are the optimal office BP values (i.e. the most protective and safe) for patients to achieve by treatment in different demographic and clinical conditions?
6. Do treatment strategies based on control of out-of-office BP provide an advantage (reduced clinical morbidity and mortality, fewer drugs, fewer side-effects) over strategies based on conventional (office) BP control?
7. What are the optimal out-of-office (home and ambulatory) BP values to be reached with treatment and should targets be lower or higher in high risk hypertensives?
8. Does central BP add to CV event prediction in untreated and treated hypertensive patients?
9. Do invasive procedures for treatment of resistant hypertension compare favourably with the best drug treatment and provide long-term BP control and reduction of morbid and fatal events?
10. Do treatment-induced changes in asymptomatic OD predict outcome? Which measures—or combinations of measures—are most valuable?
11. Are lifestyle measures known to reduce BP capable of reducing morbidity and mortality in hypertensive patients?
12. Does a treatment-induced reduction of24 h BP variability add to CV protection by antihypertensive treatment?
13. Does BP reduction substantially lower CV risk in resistant hypertension?
While RCTs remain the ‘gold standard’ for solving therapeutic issues, it is equally clear that it would be unreasonable to expect that all these questions can realistically be answered by RCTs in a foreseeable future. Approaching some of these questions, such as those of the reduction of CV morbid and fatal events by treating grade 1 hypertensive individuals at low risk for CVD or the CV event reduction of lifestyle measures, would require trials involving many thousands of individuals for a very extended period and may also raise ethical problems. Others, such as the benefit of drug treatment for white-coat hypertensives or the additional predictive power of central vs. peripheral BP may require huge investigational efforts for small prospective benefits. It appears reasonable, at least for the next years, to focus RCTs upon important—as well as more easily approachable—issues, like the optimal BP targets to be achieved by treatment, the BP values to be treated and achieved in elderly hypertensive individuals, clinical reduction of morbidity and fatal events by new approaches to treating resistant hypertension and the possible benefits of treating high-risk individuals with high normal BP. Other important issues, e.g. the predictive value of out-of-office BP and that of OD, can be approached more realistically by adding these measurements to the design of some of the RCTs planned in the near future.
With special thanks to Mrs Clara Sincich and Mrs Donatella Mihalic for their contribution.
The following entities participated in the development of this document
ESH Scientific Council: Josep Redón (President) (Spain), Anna Dominiczak (UK), Krzysztof Narkiewicz (Poland), Peter M. Nilsson (Sweden), Michel Burnier (Switzerland), Margus Viigimaa (Estonia), Ettore Ambrosioni (Italy), Mark Caufield (UK), Antonio Coca (Spain), Michael Hecht Olsen (Denmark), Roland E. Schmieder (Germany), Costas Tsioufis (Greece), Philippe van de Borne (Belgium).
ESC Committee for Practice Guidelines (CPG): José Luis Zamorano (Chairperson) (Spain), Stephan Achenbach (Germany), Helmut Baumgartner (Germany), Jeroen J. Bax (Netherlands), Hector Bueno (Spain), Veronica Dean (France), Christi Deaton (UK), Cetin Erol (Turkey), Robert Fagard (Belgium), Roberto Ferrari (Italy), David Hasdai (Israel), Arno W. Hoes (Netherlands), Paulus Kirchhof (Germany/UK), Juhani Knuuti (Finland), Philippe Kolh (Belgium), Patrizio Lancellotti (Belgium), Ales Linhart (Czech Republic), Petros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Per Anton Sirnes (Norway), Juan Luis Tamargo (Spain), Michal Tendera (Poland), Adam Torbicki (Poland), William Wijns (Belgium), Stephan Windecker (Switzerland).
Document Reviewers: Denis L. Clement (ESH Review Co-ordinator) (Belgium), Antonio Coca (ESH Review Co-ordinator) (Spain), Thierry C. Gillebert (ESC Review Co-ordinator) (Belgium), Michal Tendera (ESC Review Co-ordinator) (Poland), Enrico Agabiti Rosei (Italy), Ettore Ambrosioni (Italy), Stefan D. Anker (Germany), Johann Bauersachs (Germany), Jana Brguljan Hitij (Slovenia), Mark Caulfield (UK), Marc De Buyzere (Belgium), Sabina De Geest (Switzerland), Geneviève Anne Derumeaux (France), Serap Erdine (Turkey), Csaba Farsang (Hungary), Christian Funck-Brentano (France), Vjekoslav Gerc (Bosnia & Herzegovina), Giuseppe Germanò (Italy), Stephan Gielen (Germany), Herman Haller (Germany), Arno W. Hoes (Netherlands), Jens Jordan (Germany), Thomas Kahan (Sweden), Michel Komajda (France), Dragan Lovic (Serbia), Heiko Mahrholdt (Germany), Michael Hecht Olsen (Denmark), Jan Ostergren (Sweden), Gianfranco Parati (Italy), Joep Perk (Sweden), Jorge Polonia (Portugal), Bogdan A. Popescu (Romania), Zeljko Reiner (Croatia), Lars Rydén (Sweden), Yuriy Sirenko (Ukraine), Alice Stanton (Ireland), Harry Struijker-Boudier (Netherlands), Costas Tsioufis (Greece), Philippe van de Borne (Belgium), Charalambos Vlachopoulos (Greece), Massimo Volpe (Italy), David A. Wood (UK).
Other entities: ESC Associations: Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Heart Rhythm Association (EHRA), ESC Working Groups: Hypertension and the Heart, Cardiovascular Pharmacology and Drug Therapy, ESC Councils: Cardiovascular Primary Care, Cardiovascular Nursing and Allied Professions, Cardiology Practice.
Task Force members affiliations
Giuseppe Mancia (Chairperson)1, Robert Fagard (Chairperson)2, Krzysztof Narkiewicz (Section Co-ordinator)3, Josep Redón (Section Co- ordinator)4, Alberto Zanchetti (Section Co-ordinator)5, Michael Böhm6, Thierry Christiaens7, Renata Cifkova8, Guy De Backer9, Anna Dominic- zak10, Maurizio Galderisi11, Diederick E. Grobbee12, Tiny Jaarsma13, Paulus Kirchhof14, Sverre E. Kjeldsen15, Stéphane Laurent16, Athanasios J. Manolis17, Peter M. Nilsson18, Luis Miguel Ruilope19, Roland E. Schmieder20, Per Anton Sirnes21, Peter Sleight22, Margus Viigimaa23, Bernard Waeber24, Faiez Zannad25
1Centro di Fisiologia Clinica e Ipertensione, Università Milano-Bicocca; IRCSS, Istituto Auxologico Italiano, Milano, Italy; 2Hypertension and Cardiovascular Rehab. Unit, KU Leuven University, Leuven, Belgium; 3Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland; 4University of Valencia INCLIVA Research Institute and CIBERobn, Madrid; 5University of Milan, Istituto Auxologico Italiano, Milan, Italy; 6Klinik fur Innere Medizin III, Universitaetsklinikum des Saarlandes, Homburg/Saar, Germany; 7General Practice and Family Healthcare, Ghent University, Ghent, Belgium; 8Centre for Cardiovascular Prevention, Charles University Medical School I and Thomayer Hospital, Prague, Czech Republic Centre; 9Department of Public Health, University Hospital, Ghent, Belgium; 10College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 11Cardioangiology with CCU, Department of Translational Medical Science, Federico II University Hospital, Naples, Italy; 12University Medical Centre Utrecht, Utrecht, Netherlands; 13Department of Social- and Welfare Studies, Faculty of Health Sciences, University of Linkoping, Linkoping, Sweden; 14Centre for Cardiovascular Sciences, University of Birmingham and SWBH NHS Trust, Birmingham, UK and Department of Cardiovascular Medicine, University of Munster, Germany; 15Department of Cardiology, University of Oslo, Ullevaal Hospital, Oslo, Norway; 16Department of Pharmacology and INSERM U970, European Hospital Georges Pompidou, Paris, France; 17Cardiology Department, Asklepeion General Hospital, Athens, Greece; 18Department of Clinical Sciences, Lund University, Scania University Hospital, Malmo, Sweden; 19Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 20Nephrology and Hypertension, University Hospital, Erlangen, Germany; 21Cardiology Practice, Ostlandske Hjertesenter, Moss, Norway; 22Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK; 23Heart Health Centre, North Estonia Medical Centre, Tallinn University of Technology, Tallinn, Estonia; 24Physiopathologie Clinique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 25INSERM, Centre d’Investigation Clinique 9501 and U 1116, Universite de Lorraine and CHU, Nancy, France.
The content of these European Society of Hypertension (ESH) and European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESH or ESC. Permission can be obtained upon submission of a written request to ESH or ESC.
The ESH/ESC Guidelines represent the views of the ESH and ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
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