are there new threshold and goals in the treatment of arterial hypertension?

Are there new threshold and goals in the treatment ofarterial hypertension?Julian Segura and Luis M. Ruilope

Hypertension Unit, Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain

ABSTRACT

Background About half of the global burden of cardiovascular disease has been attributed to high blood pres-sure (BP). Worldwide, 7Æ6 million premature deaths (about 13Æ5% of the global total), 54% of strokes, and 47%of cases of ischemic heart disease were caused by high BP in 2001.

Methods and results All guidelines agree that pharmacological treatment of patients with hypertension shouldbe initiated as soon as BP rises >140 ⁄ 90 mmHg. Available data support the reduction of BP to values to<140 ⁄ 90 mmHg, but do not favor a reduction to <130 ⁄ 80 mmHg in patients with diabetes or a history of cardio-vascular disease because of the absence of evidence obtained in prospective studies.

Conclusions This review updates the controversies and challenges involved in the treatment of patients withestablished arterial hypertension, such as the progression of high-normal BP to overt hypertension, the choice ofappropriate threshold and goal BP levels, the adequate number of drugs to be used since the early stages ofhypertension, and which type of combination therapy offers most advantages to the patient.

Keywords Antihypertensive therapy, BP goals, cardiovascular risk, Threshold BP.

Eur J Clin Invest 2012

Introduction

Cardiovascular disease (CVD) is the leading cause of death

globally, accounting for 30% of all deaths worldwide [1].

Elevated blood pressure (BP) is probably the most-important,

modifiable risk factor for CVD. Findings from prospective

cohort studies have established a graded positive association

between BP and the risk of CVD, starting at 115 mmHg for

systolic BP [2]. BP contributes to the development of cardiovas-

cular and other diseases even when BP levels are normal or

high-normal (prehypertension), and the development of such

diseases accelerates with increasing levels of BP [3,4].

The effectiveness of antihypertensive therapy was initially

demonstrated in patients with systolic BP >160 mmHg, and the

results of early prospective trials were reviewed by Collins et al.

over two decades ago [5]. Around the same time, the effective-

ness of antihypertensive therapy in elderly patients (aged

>60 years) was also demonstrated [6]. The preventive capacity

of life-style changes, such as a healthy diet, has been studied in

the Dietary Approaches to Stop Hypertension (DASH) trial

[7,8] and is established for variations of the Mediterranean diet,

which has proven to reduce cardiovascular morbidity and mor-

tality [9,10]. Results of a meta-analysis from 2011 have also

shown a significant reduction in cardiovascular events associ-

ated with a reduced salt intake [11]. A complete intervention,

including life-style changes and antihypertensive drugs, is usu-

ally only considered in patients who present with hypertension

(grade 1 or higher) and in a small percentage of individuals

with high-normal BP if they have established cardiovascular or

renal disease. All other patients with prehypertension would

normally only receive advice about physical activity and diet

[3,4,12].

This review analyses the progression of high-normal BP to

overt hypertension and the associated burden of cardiovascular

and renal disease and provides an update on the controversies

and challenges involved in the treatment of patients with estab-

lished arterial hypertension, such as the choice of appropriate

threshold and goal BP levels, the adequate number of drugs to

be used since the early stages of hypertension and which type

of combination therapy offers most advantages to the patient.

Burden of disease and hypertension progression

About half of the global burden of CVD in 2001 has been

attributed to high BP (defined by Lawes and colleagues as

‡115 mmHg systolic BP) [1]. Worldwide, 7Æ6 million premature

European Journal of Clinical Investigation 1

DOI: 10.1111/j.1365-2362.2012.02658.x

REVIEW

deaths (about 13Æ5% of the total), 54% of strokes and 47% of

cases of ischaemic heart disease were caused by high BP in

2001. About half of this burden was carried by people with

hypertension, the rest by patients with lower levels of BP (115–

139 mmHg systolic BP) [1].

The progression of elevated BP into established arterial

hypertension has been clearly shown in the Framingham study

[13]. Findings from this seminal study have also demonstrated

that the prevalence of cardiovascular morbidity and mortality

is higher in individuals with normal BP than in those with opti-

mal BP and increases even more in patients with high-normal

BP [14]. With ageing, BP values – and predominantly systolic

BP values – progressively rises from normal BP levels to prehy-

pertensive levels, before advancing to established arterial

hypertension. The gradual progression of BP is also observed

when patients are not or insufficiently treated, results in the

development of atherosclerosis and target-organ damage

(TOD), and shortens the time until symptomatic CVD or renal

disease become evident.

Results of the Trial of Preventing Hypertension (TROPHY)

[15] and the Prevention of Hypertension with the Angiotensin-

Converting-Enzyme inhibitor Ramipril in Patients with

High-Normal BP (PHARAO) study [16] showed that pharma-

cological intervention with an angiotensin-receptor blocker

(ARB) or an angiotensin-converting-enzyme (ACE) inhibitor is

sufficient to prevent the progression of high-normal BP into

established arterial hypertension, probably avoiding the subse-

quent increase in cardiovascular risk. Further studies are

required to confirm these findings and to investigate whether

such an early intervention is cost-effective and prevents cardio-

vascular morbidity and mortality. However, guidelines [3,4,12]

contemplate the use of antihypertensive drugs, in particular

that of suppressors of the renin–angiotensin–aldosterone sys-

tem (RAAS) in patients with high-normal BP and TOD. Treat-

ment with antihypertensive drugs of different classes is also

used in patients with clinically overt CV or advanced renal

disease who present with BP levels <140 ⁄ 90 mmHg.

The effect of antihypertensive treatment on the secondary

prevention of cardiovascular events and all-cause mortality

among persons without clinically defined hypertension

(<140 ⁄ 90 mmHg) was evaluated in a meta-analysis published

in 2011 [17]. The investigators acknowledge that antihyperten-

sive drugs could be used for reasons other than their capacity

to lower BP as they might exert additional beneficial effects and

concluded that this type of treatment was associated with a

decreased risk of stroke, congestive heart failure, composite

CVD events, and all-cause mortality. Interestingly, cardiovascu-

lar mortality and the incidence of myocardial infarction were

not significantly lower in patients who took antihypertensive

medication with BP values <140 ⁄ 90 mmHg. Even so, the con-

clusion of the authors and an accompanying editorial was that

antihypertensive treatment was beneficial for patients with

CVD and a BP <140 ⁄ 90 mmHg [17,18].

Validity of office BP measurements

Clinicians generally agree home BP measurement should be

implemented in clinical practice together with the use of ambu-

latory BP monitoring, both of which improve the assessment of

out-of-office BP levels of patients with hypertension [3,12]. Both

methods avoid the white-coat effect, in which patients experi-

ence elevated BP in a clinical setting but not in other situations,

and also allow the diagnosis of masked hypertension. Table 1

contains data from patients with established CVD or diabetes

with accompanying TOD, comparing the values obtained by

office BP measurement and mean 24-h systolic BP [19]. Obvi-

ously, an important discrepancy exists between these two mea-

sures. These differences could help to explain the results of

several trials in which differences in BP between active therapy

and placebo were not accompanied by differences in cardiovas-

cular outcomes [20]. The initial BP of the participants in those

trials was in the range 140–150 mmHg, but office BP measure-

ments might not have expressed the out-of-office BP of these

patients. However, the BP Lowering Treatment Trialist Collabo-

ration reviewed data from 201 566 patients to determine

whether the magnitude of the benefit of reducing BP varies

with the clinical BP level [21]. The authors concluded that it

was ‘unlikely that the effectiveness of BP-lowering treatments

depends substantively upon starting BP levels’ [21].

Data obtained over the past 2 years have increased interest

in and highlighted the need of controlling BP variability

(meaning the variability between office visits) and BP instability

(that is, transient fluctuations in BP, usually in response to a

Table 1 Number of treated high-risk patients with hypertensionand percentage whose 24-h ambulatory BP is controlled*,†,‡

Office BP

(mmHg)

CHD (% of

total)

Stroke (%

of total)

Diabetes

(% of total)

<120 ⁄ 80 129 (88Æ4) 68 (82Æ9) 144 (81Æ8)

120–129 ⁄ 80–84 130 (75Æ6) 90 (73Æ2) 228 (74Æ3)

130–139 ⁄ 85–89 224 (65Æ1) 123 (59Æ7) 408 (57Æ1)

140–159 ⁄ 90–99 401 (45Æ2) 260 (43Æ0) 1142 (43Æ2)

‡160 ⁄ 100 205 (25Æ3) 126 (23Æ7) 624 (22Æ3)

Total 1089 (46Æ1) 667 (43Æ1) 2546 (38Æ3)

P value <0Æ001 <0Æ001 <0Æ001

*Defined as <130 ⁄ 80 mmHg.†According to office BP and type of disease.‡4729 patients were included in this analysis.

BP, blood pressure; CHD, coronary heart disease; TOD, target-organ damage.

2 ª 2012 The Authors. European Journal of Clinical Investigation ª 2012 Stichting European Society for Clinical Investigation Journal Foundation

J. SEGURA AND L. M RUILOPE www.ejci-online.com

specific stimulus such as stress or the lack of compliance) in

visit-to-visit BP estimation [22–24]. Different classes of antihy-

pertensive drugs have different effects on the control of long-

term BP variability, with calcium-channel blockers (CCBs)

seeming to provide the best level of control [25]. In summary,

threshold and in particular goal BP are enormously important

for adequate control of BP, and the use of home or ambulatory

BP estimations can help estimating the exact situation of the

patient and improve the information obtained through office

BP measurements. In fact, the NICE Guidelines have been

recently updated recommending ambulatory and home BP

measurement to confirm the diagnosis of hypertension [26].

Threshold and target BPs: recommendations incurrent guidelines

All guidelines agree that pharmacological treatment of patients

with hypertension should be initiated as soon as BP rises

>140 ⁄ 90 mmHg [3,4,12]. In patients with grade 1 hypertension

and low or moderate risk, a period of initial treatment with

nonpharmacological measures is recommended, with antihy-

pertensive drug therapy being initiated if this approach fails

[3]. An exception is patients with high-normal BP and a high

global cardiovascular risk owing to the presence of diabetes,

CKD or established CVD in whom guidelines recommend the

initiation of pharmacological therapy [3,4,12]. Nonetheless, in

the reappraisal of the European Society of Hypertension (ESH)

guidelines [27], the absence of evidence about the outcome of

these patients led to the recommendation that these individuals

should not be treated pharmacologically unless they have type 2

diabetes and TOD (in particular micro or macroalbuminuria).

Most trials of antihypertensive therapies that have reported

clear reductions in major cardiovascular events have included

individuals with an initial systolic BP >160 mmHg [28], and

only in a few trials was mean systolic BP lowered to <140 mmHg.

By contrast, diastolic BP of <90 mmHg for BP was achieved in

most trials [29]. However, findings from trials showing the

advantages of a BP reduction <140 ⁄ 90 mmHg, albeit incom-

plete, suggest that, in patients with hypertension, the return of

grade 1–2 BP to 130–139 ⁄ 80–89 mmHg is adequate [27]. On the

other hand, data indicate that attaining BP values

<120 ⁄ 80 mmHg can be dangerous, as indicated in the Ongoing

Telmisartan Alone and in Combination with Ramipril Global

Endpoint Trial (ONTARGET) [30], the International Verapam-

ilSR-Trandolapril (INVEST) study [31], and the Randomized

Olmesartan and Diabetes Microalbuminuria Prevention

(ROADMAP) study [32], in which cardiovascular death was

more prevalent in patients with established coronary artery

disease and systolic BP values <120 mmHg. Similarly, strict

control to systolic BP values <120 mmHg in the Action to

Control Cardiovascular Risk in Diabetes (ACCORD) study [33]

did not reduce the incidence of fatal and nonfatal cardiovascu-

lar events in patients with diabetes. These findings could

preclude the consideration of a target BP of 130 ⁄ 80 mmHg, at

least in patients with established CVD, and contrast with the

beneficial effects of antihypertensive therapy demonstrated in

the meta-analysis of studies in normotensive individuals [17].

However, in this meta-analysis, cardiovascular mortality was

similar in patients receiving antihypertensive drugs for second-

ary prevention and in untreated controls.

In patients with CKD, a low target BP of <130 ⁄ 80 mmHg (or

even lower in the presence of proteinuria) is considered appro-

priate [3,4,12]. This target BP has been questioned by results

obtained in the extension of the African American Study in

Kidney Disease (AASKD) study [34] and by data from the

ACCORD study [33], in which a target BP <120 ⁄ 80 mmHg was

not accompanied by an improvement in renal function.

Nonetheless, findings from the Action in Diabetes and Vascular

Disease: Preterax and Diamicron MR Controlled Evaluation

(ADVANCE) study [35] seem to be in favour of a low BP goal

for renal protection. A low BP target was also beneficial in

patients with hypertensive kidney disease and proteinuria [34],

but the fact that CKD and CVD are so closely related makes the

separation of cardiovascular and renal BP goals difficult in

these patients [27], as a low target BP goal that might be benefi-

cial for the kidney could be deleterious for the coronary arteries

[36].

The possibility that low BP levels are better tolerated by the

cerebral circulation than by the coronary circulation is an inter-

esting hypothesis. This concept is supported by data from

Thompson and colleagues [17], the ONTARGET [30] and

ACCORD [33] studies, as well as from a 2011 meta-analysis on

the effects of intensive BP reduction in 73 913 patients with

diabetes [37]. However, the absence of a beneficial effect of

telmisartan when compared with placebo, despite a difference

in BP between the two groups in the Prevention Regimen for

Effectively avoiding Second Strokes (PROFESS) trial [38], seems

to disagree with this hypothesis.

The evidence for the adequacy of BP targets contained in

guidelines [3,4] in antihypertensive treatment has been

reviewed [28]. Available data support the reduction in BP to

values to <140 ⁄ 90 mmHg but do not favour a reduction to

<130 ⁄ 80 mmHg in patients with diabetes or a history of CVD as

indicated by most guidelines because of the absence of evi-

dence obtained in prospective studies. The authors of the reap-

praisal of the ESH guidelines conclude that ‘on the basis of

current data, it may be prudent to recommend lowering [sys-

tolic ⁄ diastolic BP] to values within the range 130–139 ⁄ 80–

85 mmHg, and possibly closer to the lower values in this range,

in all hypertensive patients. More critical evidence from specific

randomised trials is desirable, however [27]. In summary, the

BP goal <130 ⁄ 80 mmHg has been discarded for two reasons:


ARE THERE NEW THRESHOLD AND GOALS IN THE TREATMENT OF ARTERIAL HYPERTENSION?

firstly, because no concluding evidence exists that would

support it, and, secondly, because a BP goal <130 ⁄ 80 mmHg

can be accompanied by an increased risk of cardiac events in

patients with established CAD and in whose with diabetes.

How to start treatment

For many years, the initial pharmacological treatment of arterial

hypertension was antihypertensive monotherapy, which was

then followed by one of two options: either the addition of a

second drug, if required, or the switch to another drug, in an

attempt to find the appropriate monotherapy for each individ-

ual patient (also known as ‘sequential therapy’). Administra-

tion of a combination of at least two drugs from the start of

treatment is recommended in the guidelines [3,4], particularly

in patients in whom actual BP and target BP differ by

>20 mmHg. This measure facilitates and accelerates the early

control of BP [39,40] and contributes to the maintenance of

adequate long-term BP control, as shown in the ACCOMPLISH

study [41].

The drug combination can be either administered in the form

of various individual pills or in one pill as a fixed combination,

which significantly improves compliance [39,42,43]. The most-

widely used combinations are those containing an RAAS

suppressor (such as an ACE inhibitor or an angiotensin-recep-

tor blocker) and a diuretic. However, the positive cardiovascu-

lar and renal outcomes of the ACCOMPLISH study [41,44]

greatly promoted the combined use of a RAAS suppressor and

a CCB. Irrespective of how treatment is begun, clinicians gener-

ally agree that rapid initial reduction in BP within the first

3 months of therapy is required to improve cardiovascular

outcomes [45,46].

A triple combination is needed in ‡30% of patients with

hypertension to reach the target BP [40], although it should be

acknowledged that this strategy has never been tested for the

efficacy on reducing major CV endpoints. The most frequently

used fixed triads consist of an RAAS suppressor (ACE inhibitor

or angiotensin-receptor blocker), a CCB (most commonly

amlodipine) and a thiazide diuretic (usually hydrochlorothia-

zide). The combined effects of the three drugs at optimal doses

control BP in a high percentage (>50%) of patients who require

triple therapy. Fixed combinations containing a RAAS suppres-

sor (valsartan or olmesartan), a CCB, (amlodipine) and a diure-

tic (hydrochlorothiazide) in one pill are now available [47].

Hydrochlorothiazide has been substituted by the more-potent

chlorthalidone at similar doses in several studies [48–50].

Initiation of antihypertensive therapy is a challenge in elderly

patients (>65 years), because no trial with initial BP levels

between 140 and 160 mmHg has been performed, and in no

trial with initial BP levels of >160 mmHg systolic BP went

<140 mmHg [27]. In elderly patients, the systolic BP goal

should be <140 mmHg provided that treatment is conducted

with particular attention to adverse responses to antihyperten-

sive medication [3,28]. For patients aged >80 years, the target

systolic BP should be <150 mmHg, which reflects the findings

of the Hypertension in the Very Elderly Trial (HYVET) [51].

HYVET was the first prospective trial in patients with hyper-

tension who were >80 years of age (so far, available data were

post-hoc meta-analyses of elderly patients who were included

in other trials) [52]. Data of a meta-analysis showed that antihy-

pertensive therapy diminished nonfatal cardiovascular events,

in particular stroke, but not cardiovascular death. The results of

HYVET indicated that lowering BP to a goal <150 mmHg

prevented fatal and nonfatal events. The treatment was initi-

ated with a diuretic (indapamide), and in >80% of patients

combined with an ACE inhibitor (perindopril) to achieve target

BP. More recently, the ESPORT study describes that, in elderly

patients with essential hypertension, olmesartan provides an

effective, prolonged and well-tolerated BP control in compari-

son with ramipril as first-line antihypertensive drug [53].

Another challenge in the treatment of elderly patients with

hypertension is the presence of orthostatic hypotension, which

is defined as a decrease >20 mmHg in systolic BP or of

>10 mmHg in diastolic BP when a person moves from a supine

to a sitting or standing position. Orthostatic hypotension is

particularly prevalent in elderly, occurring in up to 26% of

individuals aged >85 years who have hypertension [54]. The

presence of orthostatic hypotension is a predictor of cardiovas-

cular events [54], precipitates intercurrent complications (such

as falls) and requires a reconsideration of antihypertensive

treatment in elderly patients [55]. The need for a trial in elderly

hypertensives with orthostatic hypotension in that the discon-

tinuation of antihypertensive therapy is compared with contin-

ued treatment has been highlighted [56]. Elderly patients with

hypertension require close medical attention. Antihypertensive

therapy should be initiated slowly, using lower doses than

usual, which are then slowly titrated up. A combination with

other drugs can be required in many patients, as shown in

HYVET [51]. BP has to be measured sitting and standing to

discard orthostatism. As many elderly patients require

polymedication because of comorbidities, drug–drug interac-

tions can make it more difficult to achieve compliance and

long-term adherence.

Conclusions

Many important decisions in hypertension management are

taken without the support of evidence from large, randomised

controlled trials [3]. As a consequence, further studies are

needed, in particular trials comparing the effectiveness of life-

style changes and of antihypertensive drug therapy in patients

with grade 1 hypertension. Drug-based trials need to include



elderly patients with grade 1 hypertension and patients with

high-normal BP levels at baseline. The need to attain a target BP

<130 ⁄ 80 mmHg to prevent future cardiovascular events and

death in patients without established CVD should also be

investigated. The problem with these new trials is the high

number of patients required and, as a consequence, their high

cost that will complicate their execution. Future studies must

also contemplate the simultaneous evolution of CVD and renal

disease. Investigation of this issue will improve our knowledge

of how the treatment of arterial hypertension and its associated

risk factors affect the interlinked development of cardiovascu-

lar and renal problems. The results of the ADVANCE [35,57]

and ACCOMPLISH [41,44] studies have shown that the same

medication improved both cardiovascular [41,57] and renal

outcome [35,44].

Key to the successful clinical management of hypertension is

attaining the best BP control among patients with hypertension

after having adequately established that BP is elevated and

whether other cardiovascular risk factors exist [58]. The long-

term benefits of an adequate management of hypertension in a

given patient are determined by the stage of cardiovascular and

renal disease when treatment is initiated and on the basis of the

adequacy of the simultaneous control of other coexisting

cardiovascular risk factors [59].

Although office BP measurement will remain the most-

widely used method to assessing patients in the foreseeable

future, ambulatory BP monitoring and home BP measurement

can replace office BP readings when available. The develop-

ment of novel therapeutic targets for hypertension is needed

[60,61]. Novel pharmacological approaches are targeted

towards treating resistant hypertension, improving BP control

and reducing cardiovascular risk beyond that achieved by

BP-lowering alone.

Address

Hypertension Unit, Department of Nephrology, Hospital 12 de

Octubre, Madrid, Spain (J. Segura, L. M. Ruilope).

Correspondence to: Dr Luis M Ruilope, Hypertension Unit,

Department of Nephrology, Hospital 12 de Octubre, Av.

Cordoba s ⁄ n, 28041 Madrid, Spain. Tel.: +34913908198;

fax: +34913908035; e-mail: [email protected].

Received 7 December 2011; accepted 2 February 2012

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are there new threshold and goals in the treatment of arterial hypertension?

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