Impact of new clinical trials on recent guidelines on hypertension management

Abstract

Guidelines on hypertension diagnosis and treatment have been issued in 2007. Since then, a number of major intervention clinical trials have been designed, carried out, and completed with the aim of investigating unsolved issues related to the impact of the blood pressure-lowering intervention on cardiovascular risk and events. These include, among others, the nephroprotective properties of antihypertensive drugs, the blood pressure targets to be achieved during treatment in uncomplicated and more so in complicated hypertensive patients, the advantages of one drug combination versus another, and the benefits of antihypertensive drugs in the very elderly. All these questions have received a clear-cut answer by the results of recently performed clinical trials, which have been included in the 2009 update document of the European guidelines. This paper will be focused on the 2007 guidelines document and the 2009 update paper, highlighting the new concepts and recommendations provided by the most recent intervention trials.

Key words::

• Antihypertensive treatment
• clinical trials
• guidelines

Key messages

• Assessment of target organ damage and quantification of total cardiovascular risk is an important step aimed at optimizing the decision about treatment initiation, intensity, and goals.

• Treatment should start at blood pressure ≥ 140/90 mmHg and should allow the values to be lowered to 130–139/80–85 mmHg, particularly in high-risk patients.

• Combination drug treatment should be implemented, given the evidence that only this approach can allow proper blood pressure control to be achieved.

Following the publication of the 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines (1), several important new clinical outcome trials in the field of hypertension treatment have been completed and published (Figure 1). These include the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS), the Telmisartan Randomized Assessment study in ACE-I intolerant subjects with cardiovascular disease (TRANSCEND), the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular disease Preterax and Diamicron-MR Controlled Evaluation (ADVANCE), the Hypertension in the Very Elderly Trial (HYVET), and the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) (2–8). During the past few months the list has been further increased with the presentation at major international scientific meetings of the results of the Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) trial, whose major findings have been published in abstract form (9). These trials addressed important questions related to antihypertensive treatment, such as the metabolic and renal protection in the hypertensive patient, the therapeutic approach in very elderly hypertensives, the advantages of the pharmacological intervention based on the blockade of the renin–angiotensin system, as well as the future perspectives of combination drug treatment. The results of the above-mentioned major intervention trials led the Task Force Committee for European Society of Hypertension Guidelines to update the paper issued in 2007, with the publication of the 2009 European Society of Hypertension document (10). This document represents therefore an example on how new clinical trials may integrate and modify the recommendations provided by guidelines on a specific clinical condition.

Figure 1. Recent clinical trials, identified by acronyms and related areas of intervention in the field of antihypertension treatment. TRANSCEND = Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; PROFESS = Prevention Regimen for Effectively Avoiding Second Strokes; ONTARGET = Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular disease, Preterax and Diamicron-MR Controlled Evaluation; HYVET = Hypertension in the Very Elderly Trial; ACCOMPLISH = Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension; ROADMAP = Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention.

This paper will examine the impact of recent clinical studies on hypertension guidelines. After briefly highlighting the key points of the 2007 ESH/ESC guideline recommendations on hypertension diagnosis and treatment, the paper will then discuss the elements of novelty of the 2009 update document and the contribution of recent clinical trials to these recommendations. Special emphasis will be finally placed on the unsolved issues of hypertension treatment and on the possible contribution future clinical trials may provide to clarify these areas of major clinical relevance.

The ESH/ESC 2007 Guidelines

The 2007 ESH/ESC Hypertension Guidelines have developed a number of new recommendations focused on the diagnostic and therapeutic approach to the hypertensive disease. These innovative elements (summarized in Table I) will be examined in the following paragraphs.

Table I. Elements of novelty in 2007 European Guidelines.

Cardiovascular risk factors and overall riskRelevance of subclinical target organ damage assessmentThresholds of blood pressure values and treatment goal standardPharmacological and non-pharmacological therapeutic strategiesCombination treatment as first-choice treatmentTherapeutic impact of antihypertensive drugs on metabolic profile

Total cardiovascular risk profile

A number of ‘new’ cardiovascular risk factors have been included in the 2007 guidelines document (1). First, greater attention has been given to stricter cholesterol and triglycerides control, as well as to the overweight/obesity-related risk. Emphasis has been given to the presence of visceral obesity, i.e. a condition which is associated with a greater degree of insulin resistance and a significantly greater overall cardiovascular risk as compared to peripheral obesity (11). Second, the so-called metabolic syndrome, regarded as the constellation of several pathological factors (dyslipidaemia, visceral obesity, insulin resistance, hypertension, and hyperglycaemia), was specifically mentioned because of its ability to increase markedly the overall cardiovascular risk (12). Two further elements of novelty deserve to be mentioned, namely: 1) the importance of subclinical target organ damage, considering its high prevalence in hypertension and its unfavourable prognostic impact (13), and 2) the ‘declassification’ of C-reactive protein as a risk factor, probably because the prognostic significance of this index in terms of cardiovascular events suffers from the influence of other biochemical variables (14).

Target organ damage

The elements of novelty in this particular topic of the ESH/ESC 2007 guideline document refer to three specific issues (1). First, emphasis is given to the assessment of the subclinical organ damage, since several studies have documented the adverse prognostic impact exerted in hypertensive patients by various markers of target organ damage. Second, a cost-effectiveness analysis of different methods to assess target organ damage has been proposed, based on their predictive significance for future cardiovascular events, their availability in clinical practice, and economic impact. The analysis of these factors confirms the recommendation to prefer the use of simple but reliable markers, such as microalbuminuria. This indeed represents the expression of generalized vascular damage, reflecting the presence of other types of organ damage, such as cardiac hypertrophy, vascular hypertrophy, and endothelial dysfunction. As will be discussed later, the relevance of microalbuminuria as marker of end-organ damage, and more generally as index of cardiovascular risk, is confirmed by the fact that in some recent trials, such as the ROADMAP (9), the onset of microalbuminuria represents the primary objective of the study. Finally, the 2007 guidelines recommend periodical reassessment of target organ damage during antihypertensive treatment in order to identify more precisely the reduction of cardiovascular risk induced by treatment.

Threshold blood pressure levels and targets for antihypertensive treatment

As mentioned above, European guidelines stress the importance of blood pressure values in the so-called ‘normal/high’ range, based on the evidence (also collected by the Framingham study) that this condition is not an innocent phenomenon but rather already carries an increase in cardiovascular risk (15). A further aspect of specific practical relevance, which will be mentioned in the section devoted to the pharmacological intervention, is that the blood pressure threshold defining the need to start antihypertensive treatment is flexible, depending on the patient's global cardiovascular risk profile.

The European guidelines stress the importance of the so-called ‘alternative pressures’ (as compared to the traditional sphygmomanometric ones), which include ambulatory and home blood pressure values, based on the information collected in recent intervention trials and clinical studies. These include the evidence that 1) both ambulatory and home blood pressure values are closely related to prognosis (16); 2) their assessment may be useful not only in untreated subjects, but also in treated patients with the aim of monitoring the effects of antihypertensive treatment and increasing patient's compliance to drug therapy; and 3) they allow two specific clinical conditions to be diagnosed, namely ‘white-coat’ or isolated clinic hypertension, characterized by high office blood pressure with normal ambulatory blood pressure values, and ‘masked’ hypertension, characterized by normal office blood pressure with high ambulatory blood pressure values (16,17).

The 2007 guidelines strongly emphasize that since the primary goal of antihypertensive treatment is represented by the blood pressure reduction per se, the choice of the specific antihypertensive compound to be used as first-line therapy becomes less relevant, also because a combination therapy strategy is frequently required (1,14,18). As previously mentioned, combination treatment becomes particularly important in hypertensive patients at high cardiovascular risk and/or in those in whom high blood pressure is complicated by diabetes mellitus, coronary heart disease, or renal insufficiency. The 2007 guidelines recognize the importance of both pharmacological and non-pharmacological approaches to hypertension treatment. The use of one or both these therapeutic measures (which will be briefly mentioned below) depends not only on the severity of the blood pressure elevation but also on the presence of added cardiovascular risk factors, target organ damage, or concomitant diseases, i.e. on the patient's global cardiovascular risk profile.

Finally, it remains to be stressed that the emphasis given by the 2007 guidelines to the concept of ‘blood pressure control’ is based on the evidence that a strict blood pressure reduction improves a patient's prognosis. To this aim, however, also regression of target organ damage contributes, implying that both the effectiveness of antihypertensive treatment and the direct effects of the drugs in terms of cardiovascular protection (the so-called ‘ancillary properties’) (18) may contribute to determining the beneficial effects of the blood pressure-lowering intervention. It is likely, however, that the protective effects associated with the ancillary properties of antihypertensive drugs achieve importance on a long-term basis, i.e. during several years of therapy, while in the early stages of treatment a prompt achievement of an optimal blood pressure control seems of top priority (1,10).

Pharmacological and non-pharmacological therapeutic strategies

The 2007 hypertension guidelines highlight the usefulness of non-pharmacological therapeutic interventions as measures capable of lowering blood pressure values and favourably interfering with the cardiovascular risk profile. The guidelines also emphasize the usefulness of these approaches in preventing the risk of future development of hypertension, thereby recommending their use in patients with blood pressure values in the ‘normal/high’ range. Among the various non-pharmacological measures mentioned in the document, particular relevance is given to dietary sodium restriction, hypocaloric diet, and physical exercise. These two latter measures, besides a moderate blood pressure reduction (on average 5–7 mmHg and 3–4 mmHg for systolic and diastolic blood pressure, respectively), guarantee other beneficial effects, such as the improvement of insulin sensitivity, weight loss, and antiatherogenic and sympatho-moderating effects (19). Along with their favourable properties, non-pharmacological measures also have potential limitations and disadvantages. For example, it has been noted that after a few weeks or months, they frequently are no longer followed by the patient, also reducing the compliance of the subject to the initiation of pharmacological treatment.

As far as pharmacological treatment is concerned, the 2007 guidelines do not classify the various available classes of antihypertensive drugs in order of preference. On the contrary, they recommend that the choice of therapeutic drug in clinical practice is based on the characteristics of the patient, on cardiovascular risk profile, and on the presence of target organ damage and/or associated clinical conditions. As possible therapeutic choice, the 2007 guidelines include five drug classes, namely ACE inhibitors, beta-blockers, diuretics, calcium antagonists, and angiotensin II receptor antagonists. This statement is in sharp contrast with the British guidelines recommendations (which discourage the use of beta-blockers) (20), because the European guidelines 1) raise the priority of achieving an effective blood pressure control, regardless of the type of drug used to achieve it, and 2) differentiate, within the broad class of beta-blockers, those most recently synthesized compounds, characterized by specific vasodilatory properties. Compared to ‘classic’ beta-blockers, these drugs display favourable properties such as glucose-neutral (and in some cases even favourable) metabolic effects as well as improvement of endothelial function.

The guidelines also emphasize the importance of diuretic agents, particularly when combined with other drugs, in achieving blood pressure control. However, the guidelines do not take a position on the recent debate related to the possible differences between various compounds belonging to the thiazide diuretic class, and more specifically to the hypothesized superiority in term of efficacy of chlorthalidone as compared to hydrochlorothiazide (21,22). The data available on this issue, however, are conflicting, and no prospective study is available on the long-term effects of the two drugs on cardiovascular outcomes.

Specific role of different classes of antihypertensive drugs and combination treatment

As mentioned above, the 2007 European guidelines strongly emphasize that the primary goal of treatment is to lower blood pressure values per se, since the benefit of the treatment primarily depends on the achievement of blood pressure values as close as possible to 140/90 mmHg (and possibly lower). Therefore, if the primary goal of treatment is the blood pressure ‘normalization’, the crucial question is not any more the decision of which pharmacological class needs to be used as first-choice treatment—an adequate blood pressure control almost invariably involving the use of a combination therapy. This priority is even more evident in hypertensive patients with diabetes, coronary artery disease, and, in general, in patients at high or very high cardiovascular risk, as the standard goal for antihypertensive treatment is positioned around 130/80 mmHg (see below).

Particular attention should be paid, however, to some unfavourable metabolic properties of certain classes of antihypertensive drugs (diuretics and beta-blockers), whose administration is not indicated as first-choice therapy in patients with pre-diabetes, obesity, or in conditions which may favour the development of metabolic abnormalities, including insulin resistance (23).

The 2007 guidelines document emphasizes the need for combination therapy when monotherapy is unable to ‘normalize’ blood pressure values (1), an event that unfortunately frequently occurs in current clinical practice. This is true to a greater extent in patients at high cardiovascular risk, requiring a tighter blood pressure control in order to guarantee a greater protection against target organ damage and cardiovascular events. The guidelines also mention the preferred pharmacological antihypertensive combinations. They include (Figure 2):

Figure 2. Possible combinations between some classes of antihypertensive drugs. The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled intervention trials. Modified from Mancia et al. 2007 (1).

• Thiazide diuretics and ACE inhibitors

• Thiazide diuretics and angiotensin II receptor blockers

• Calcium antagonists and ACE inhibitors

• Calcium antagonists and angiotensin II receptor blockers

• Calcium antagonists and thiazide diuretics

• Beta-blockers and calcium antagonists (dihydropyridine)

It is clear that associations based on the use of drugs acting on the renin–angiotensin system represent the combination therapy that, in terms of flexibility of use, efficacy, and cost-benefit ratio, better suit antihypertensive treatment in different clinical conditions characterized by a medium, a high, or a very high cardiovascular risk. Within the class of drugs acting on the renin–angiotensin system, however, evidence exists that treatment compliance appears to be higher for angiotensin II receptors blockers than for ACE inhibitors, a feature responsible for the lower discontinuation rate reported with the former compounds (24).

Blood pressure control

Despite remarkable improvement in cardiovascular prevention achieved through antihypertensive therapy, the cardiovascular risk profile of hypertensive patients (and therefore the number of fatal and non-fatal cardiovascular events) still remains higher than that characterizing age-matched normotensive subjects (25,26). Several hypotheses have been advanced over the years to explain this apparently paradoxical phenomenon. Among these, two gained greater popularity (27). The first one refers to the facts that cardiovascular risk of hypertensive patients is only partly modifiable and that cardiovascular morbidity and mortality remain higher in both untreated and treated hypertensive patients than in normotensive subjects. It is likely that this depends on the fact that structural and functional hypertension-related cardiovascular alterations are only partially reversible by antihypertensive treatment. The second hypothesis, however, relates this phenomenon to the lack of optimal therapeutic blood pressure control. In this regard, a number of observational and intervention studies highlighted the difficulty to achieve in treated hypertensive patients a real ‘normalization’ of blood pressure values (below 140/90 mmHg). This difficulty is confirmed by the results of controlled clinical trials performed in hypertensive patients, in which only a small proportion of patients displays a satisfactory systo-diastolic blood pressure control (28). The situation is even clearer in everyday clinical practice. Indeed the results of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study (29) show that the non-optimal blood pressure control 1) mainly involves systolic blood pressure values, and 2) is confirmed independently on the different (sphygmomanometric, home, and ambulatory) blood pressure measurements used. Three additional aspects of the problem deserve to be mentioned. First, the difficulty to achieve and to maintain blood pressure values below 140/90 mmHg through the years is independent of whether general practitioners or specialists take care of the patient (30–32). Second, the unsatisfactory blood pressure control affects not only hypertensive patients at low cardiovascular risk but also, and to a greater extent, those with a high risk profile (30). Third, a recent analysis of the European Lacidipine Study on Atherosclerosis (ELSA) data (33) highlights that not only is it difficult to achieve a satisfactory blood pressure control, but it is also very demanding (both for the physician and the patient) to maintain such a control, once achieved, over the years. This has important unfavourable clinical consequences, responsible, as already mentioned, for the persistently high cardiovascular morbidity and mortality seen in treated hypertensive patients. Finally, the common feature of all these situations is presumably the limited use of combination therapy which, on the contrary, has to be considered as one of the corner-stones for obtaining optimal blood pressure control.

Implementation of guidelines

In the European document a very topical issue is finally addressed, namely how to implement guidelines in everyday clinical practice. For example, the document stresses the importance of active participation of medical (especially the general practitioners) and paramedical staff in strategies of cardiovascular prevention and, more in general, in the patient's educational process. It also emphasizes the potential importance of specialized nursing staff active in that field, who may be able to address the easiest diagnostic and therapeutic aspects and to determine cardiovascular risk with the aid of risk charts (34).

The update document 2009 and the impact of new trials

The update document 2009 (10) focuses on seven major areas of interest. They include: 1) assessment of target organ damage, 2) total cardiovascular risk, 3) blood pressure threshold for treatment and blood pressure goals of the therapeutic intervention, 4) therapeutic strategies, 5) combination drug treatment, 6) associated clinical conditions, and 7) poly-pill. Some of these issues will be briefly discussed hereafter.

Assessment of target organ damage

One of the most relevant concepts discussed in the 2009 guidelines document refers to the need to count in clinical practice on diagnostic procedures capable of detecting end-organ damage, with a low economic impact and throughout a feasible approach. In general the update document emphasizes the importance of an electrocardiogram for the assessment of left ventricular hypertrophy, with a particular mention of the so-called ‘electrocardiographic strain pattern’, which carries an important prognostic relevance (35). Other markers of organ damage include microalbuminuria and the modified diet in renal disease (MDRD) formula with the aim at detecting earlier alterations in renal function (10). The search for simpler examinations does not detract importance from other well established approaches (echocardiography, carotid ultrasonography, cerebral imaging) to evaluate end-organ damage. It rather underlines the attempt, by using less expensive approaches, to use in clinical practice markers of organ damage of reduced economic cost.

Cardiovascular risk profile

The update document 2009 (10) addresses the question as to whether the presence of early cardiac, vascular, or renal alterations should shift the risk profile into a higher category even if the alterations are clinically not manifest. The question received a positive answer, because many studies provided evidence that this condition (which is quite common in clinical practice) carries an elevated risk of fatal and non-fatal cardiovascular events. This is the case even when blood pressure values are in the ‘high/normal’ range, i.e. between 135–139 systolic and 85–89 diastolic.

The high or very high risk category, i.e. the condition characterized by a 20% chance to develop over the next 10 years a fatal or a non-fatal cardiovascular event, has been a matter of specific studies, such as the ONTARGET, the TRANSCEND, as well as the PROFESS trial (2–4), whose results have allowed better definition of the therapeutic approach to this condition. As far as the ONTARGET results are concerned, evidence has been provided that in the high or very high risk category drugs acting on the renin–angiotensin system, such as angiotensin II receptor blockers and ACE inhibitors, provide similar favourable effects on cardiovascular events (2). A further result of the ONTARGET trial refers to the possibility that different therapeutic regimens have a different impact on discontinuation of antihypertensive treatment, i.e. a phenomenon which may contribute to the low adherence to pharmacological treatment. ONTARGET data show indeed that the discontinuation rate is significantly lower in patients treated with an angiotensin II receptor blocker than in those treated with an ACE inhibitor (2).

A final issue addressed by the 2009 document refers to the prognostic relevance of the drug-induced alterations in end-organ damage. The results of the LIFE study strongly support the concept that treatment-induced changes in left ventricular structure may be associated with an improvement in prognosis in treated hypertensive patients (36).

Blood pressure threshold and blood pressure goals of the therapeutic intervention

The 2009 document confirms the cut-off values of 140/90 mmHg for initiating antihypertensive treatment, provided that the cardiovascular risk profile is within the normal range or only modestly increased. In presence of co-morbidities (particularly diabetes mellitus, history of stroke, coronary artery disease, or renal insufficiency) these cut-off limits are set at a lower level, 130–139 mmHg for systolic and 85–89 mmHg for diastolic.

One element of novelty, however, refers to the fact that the update document 2009 does not provide evidence in favour of reaching low blood pressure values during treatment (i.e. < 130/80 mmHg) even in high-risk patients. This is because no trial published so far has shown greater benefits by achieving such values during treatment. A more prudent behaviour is to lower blood pressure values as much as possible below 140/90 mmHg. This prudent approach should allow reduction of the risk of the so-called ‘J curve’, i.e. a rebound of cardiovascular events when blood pressure during treatment goes below 120–125 mmHg for the systolic and 70–75 mmHg for diastolic, which has been suggested to take place by the results of some recent intervention trials (Figure 3) (2,37–39).

Figure 3. Relationships between systolic blood pressure (SBP), diastolic blood pressure (DBP) values, and cardiovascular (CV) events and hazard ratios (HR) in four different recent clinical trials. Note that at low systo-diastolic blood pressure (<120–125/70–75 mmHg) there is a paradoxical increase in CV events. CAD = coronary artery disease; INVEST = International Verapamil SR/Trandolapril study; ONTARGET = Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; VALUE = Valsartan Antihypertensive Long-term Use Evaluation; TNT = Treating to New Targets. Modified from Yusuf et al. 2008, p. 37–39 (2).

Therapeutic strategies and combination drug treatment

Because blood pressure reduction represents the primary goal of the therapeutic intervention, the question of which drug is to be used to achieve such a goal appears to the update guidelines 2009 less important. In addition, since very often blood pressure goals are values well below 140/90 mmHg, the use of a two-drug combination is almost mandatory. Among the various combinations the most effective ones are represented by an angiotensin II receptor blocker plus a diuretic, an ACE inhibitor plus a diuretic, an angiotensin II receptor blocker plus a calcium channel antagonist, or an ACE inhibitor combined with a calcium channel blocker. The effectiveness of this latter combination has been confirmed by the results of the recently published ACCOMPLISH study, whose results have documented the superiority of the amlodipine/benazepril combination versus benazepril/hydrochlorothiazide in achieving blood pressure control in high-risk patients (40). This is also the case for the effects of the combination in slowing down the progression of renal failure in the same group of patients. Caution should be taken when combining an ACE inhibitor plus an angiotensin II receptor blocker, since in the ONTARGET study this combination drug treatment has been shown to increase cardiovascular events and worsen renal function (2).

Treatment of associated clinical conditions

In the 2009 document particular attention has been paid to clinical conditions frequently complicating the hypertensive state. These include: 1) the very elderly, 2) diabetes mellitus, 3) previous stroke and/or myocardial infarction, and 4) renal insufficiency and failure. As far as treatment of hypertension in the very elderly is concerned, evidence has been provided by the recently published HYVET trial (7) that even in subjects aged 80 years or more, treatment of high blood pressure values is rewarding. This is documented by the trial evidence that in the actively treated elderly hypertensives achievement of systo-diastolic blood pressure values amounting to 144/78 mmHg leads to a significant reduction of all major cardiovascular end-points, including heart failure (-64%) and total fatal events (-21%). A second issue related to the treatment of hypertension in the presence of associated clinical conditions refers to diabetes mellitus. In these patients, the recent results of the ADVANCE trial (41) clearly indicate that antihypertensive treatment may exert clear-cut nephroprotective effects. It is likely that these effects are detectable in patients with diabetes and high/ normal blood pressure values.

Regarding the impact of antihypertensive treatment, and particularly angiotensin II receptor blockers, on the development and progression of renal dysfunction, recent results of the ROADMAP trial provide evidence that in diabetic patients pharmacological blockade of the angiotensin II receptors is accompanied by a significant reduction (-23%) in the incidence of new-onset microalbuminuria (9). This finding may therefore be taken as a further demonstration in favour of the concept that the choice of antihypertensive drugs for hypertension treatment should be based on the specific properties (and thus indications) of the drugs rather than ranking them for a general use (Figure 4).

Figure 4. Criteria for selecting antihypertensive drugs in current clinical practice. AF = atrial fibrillation; ARB = angiotensin II receptor blockers; CA = calcium antagonist; CHF = congestive heart failure; DM = diabetes mellitus; ESRD = end-stage renal disease; HT = hypertension; MA = microalbuminuria; MI = myocardial infarction; MS = metabolic syndrome; PAD = peripheral artery disease; RAS = renin–angiotensin system; TOD = target organ damage; LVH = left ventricular hypertrophy.

Future clinical trials and new guidelines

According to the evidence discussed in the 2009 update document (10), a number of issues concerning antihypertensive treatment will need to be addressed by future clinical trials, with results of potential major importance in the context of the new ESC/ESH guidelines. Special focus should be placed, according to the 2009 document (10), on the following questions:

1. What is the optimal blood pressure goal for prevention of recurrent stroke?

2. Should antihypertensive drugs be prescribed to all patients with grade 1 hypertension, even when total cardiovascular risk is relatively low or moderate?

3. Should antihypertensive drugs be prescribed to the elderly with grade 1 hypertension, and should antihypertensive treatment achieve a goal of below 140/90 mmHg also in the elderly?

4. Should antihypertensive drug treatment be started in diabetic patients or in patients with previous cerebrovascular or cardiovascular disease when blood pressure is still in the high/normal range, and should the blood pressure goal be below 130/80 mmHg in these patients?

5. What are the lowest safe blood pressure values to be achieved by treatment in different clinical conditions?

6. Are life-style interventions known to reduce blood pressure capable of decreasing morbidity and mortality rate in hypertension?

Results of clinical trials designed to address the above-mentioned questions will provide more solid evidence in favour of current recommendations.

Declaration of interest: The authors state no conflict of interest and have received no payment in preparation of this manuscript.