REVIEWS

Key advances in antihypertensive treatment

Ludovit Paulis, Ulrike M. Steckelings and Thomas Unger
Abstract | Although various effective treatments for hypertension are available, novel therapies to reduce
elevated blood pressure, improve blood-pressure control, treat resistant hypertension, and reduce the
associated cardiovascular risk factors are still required. A novel angiotensin-receptor blocker (ARB) was
approved in 2011, and additional compounds are in development or being tested in clinical trials. Several of
these agents have innovative mechanisms of action (an aldosterone synthase inhibitor, a natriuretic peptide
agonist, a soluble epoxide hydrolase inhibitor, and an angiotensin II type 2 receptor agonist) or dual activity
(a combined ARB and neutral endopeptidase inhibitor, an ARB and endothelin receptor A blocker, and an
endothelin-converting enzyme and neutral endopeptidase inhibitor). In addition, several novel fixed-dose
combinations of existing antihypertensive agents were approved in 2010–2011, including aliskiren double and
triple combinations, and an olmesartan triple combination. Upcoming fixed-dose combinations are expected
to introduce calcium-channel blockers other than amlodipine and diuretics other than hydrochlorothiazide.
Finally, device-based approaches to the treatment of resistant hypertension, such as renal denervation
and baroreceptor activation therapy, have shown promising results in clinical trials. However, technical
improvements in the implantation procedure and devices used for baroreceptor activation therapy are required
to address procedural safety concerns.
Paulis, L. et al. Nat. Rev. Cardiol. 9, 276–285 (2012); pubished online 20 March 2012; doi:10.1038/nrcardio.2012.33

Introduction
Hypertension is the most-prevalent controllable disease testing, and another is in phase II trials (Table 2); and
in the adult populations of developed countries and finally, nonpharmacological strategies, such as renal
contributes substantially to morbidity and mortal- denervation or baroreflex activation. In this Review, we
ity. 1 The armamentarium of antihypertensive treat- focus on developments in these three strategies in the
ment comprises diuretics, calcium-channel blockers, past 2 years (2010–2011).
β‑blockers, and inhibitors of the renin–angiotensin–
aldosterone system (RAAS) that act at various levels Novel molecules
of the RAAS cascade.2 Previously, we have speculated Only one novel molecule—the AT1R blocker azila­sartan
that novel therapeutic targets might still exist within the medoxomil—has been approved for the treatment of
RAAS.2 Indeed, the only new antihypertensive molecule hypertension in the past 2 years. However, eight new
approved in 2010–2011 was the angiotensin II type 1 compounds are currently undergoing clinical testing
receptor (AT1R) blocker azilsartan (Table 1), 3,4 which (Table 1). Two are modified versions of currently used
increases the already broad choice of this class of agents. antihypertensive drugs: a controlled-release formulation
With such a modest advance in therapeutic options, of the α2-adrenergic agonist clonidine and a modified-
the goals for new antihypertensive treatments remain release formulation of the calcium-channel blocker
unchanged: improvement of blood-pressure control; lercandipine. The other six are novel molecules: two
treatment of resistant hypertension; and possibly also dual-action AT1R blockers (known as LCZ 696, which
Institute of
Pathophysiology, reduction of cardiovascular risk factors other than blood also inhibits neutral endopeptidase, and PS 433540,
Faculty of Medicine, pressure, such as myocardial hypertrophy, fibrosis, or which also blocks the endothelin A receptor), a dual
Comenius University,
Sasinkova 4, 811 08,
increased arterial stiffness.2 The approaches to achieve endothelin-converting enzyme (ECE) and neutral
Bratislava, Slovakia these goals include development of novel molecules or endopeptidase inhibitor (known as daglutril), an aldo-
(L. Paulis), Center for new formulations, of which eight are currently in clini- sterone synthase inhibitor (known as LCI 699), a natri-
Cardiovascular
Research, Charité- cal studies (Table 1);5 intensive investigation of novel uretic peptide receptor A (NPRA) antagonist (known
Universitätsmedizin, fixed-dose combinations, of which 10 were approved as PL 3994), and a soluble epoxide hydrolase inhibitor
Hessische Strasse
3–4, 10115 Berlin,
in 2001–20096 and two in 2010, one is pending clinical (known as AR 9281). This list of eight new compounds
Germany is considerably shorter than it was in 2009, when 28 dis-
(U. M. Steckelings, tinct molecules were listed to be in the clinical phase
T. Unger).
Competing interests of investigation.2 Another novel molecule, the angio­
T. Unger and U. M. Steckelings declare an association with the
Correspondence to: tensin II type 2 receptor (AT2R) agonist compound 21,
T. Unger following company: Vicore Pharma. See the article online for
thomas.unger@ full details of the relationship. L. Paulis declares no has shown promising results in animal models but has
charite.de competing interests. not yet been tested in clinical trials.

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 FOCUS ON HYPERTENSION

AT1R blockers Key points

Strong evidence indicates that AT1R blockers are at least
■■ In 2010–2011, one novel antihypertensive—azilsartan—as well as several
as effective as β‑blockers, calcium-channel antagonists,
novel fixed-dose combinations of existing antihypertensive agents, including
or angiotensin-converting enzyme (ACE) inhibitors aliskiren double and triple combinations and an olmesartan triple combination
in reducing cardiovascular morbidity and mortality.7–9 were approved
The approval of azilsartan medoxomil in 2011 increased ■■ Novel antihypertensive compounds in clinical development include an
the number of currently available agents in this class to aldosterone synthase inhibitor, a natriuretic peptide agonist, and a soluble
eight.2 Approval of azilsartan was on the basis of ran- epoxide hydrolase inhibitor
domized studies involving almost 6,000 patients with ■■ An angiotensin II type 2 receptor agonist—compound 21—is in preclinical
development
mild-to-severe hypertension,10,11 which showed that an
■■ Novel antihypertensives with dual activity, including an angiotensin-receptor
80 mg dose of this agent was more effective than placebo blocker and neutral endopeptidase inhibitor, an angiotensin-receptor blocker
and more effective than an active comparator therapy and endothelin receptor A blocker, and an endothelin-converting enzyme and
(valsartan 320 mg or olmesartan medoxomil 40 mg) in neutral endopeptidase inhibitor, are in clinical development
lowering 24 h mean blood pressure. The antihypertensive ■■ Upcoming fixed-dose combinations of antihypertensives are expected to include
effect was sustained after 26 weeks of administration.10,11 calcium-channel blockers other than amlodipine, and diuretics other than
However, in common with other novel AT1R blockers, hydrochlorothiazide (which are included in the current combinations)
insufficient long-term morbidity and mortality data are ■■ Nonpharmacological approaches for the treatment of resistant hypertension—
renal denervation and baroreceptor activation—have shown promising results
yet available for comparison with those of established
in clinical trials
compounds, such as valsartan, losartan, and telmisartan.
Despite their efficacy, the large number of AT1R
blockers already available and the strong competition phase II study in patients with primary hypertension,
in this field is likely to discourage the launch of new 0.25 mg, 0.5 mg, or 1 mg once daily, or 0.5 mg twice daily
compounds in this class. Perhaps for this reason, several of LCI 699 reduced ambulatory systolic and diastolic
compounds that have shown promise in animal models, blood pressure as well as mean sitting systolic blood
such as PF‑03838135 and K‑868,12 have not yet entered pressure.25 However, the most profound reductions were
the clinical phase. observed with the 1 mg once daily dose, which was the
only regimen that also reduced mean sitting diastolic
Aldosterone synthase inhibitors blood pressure. This dosage achieved a blood-pressure
The recognition of aldosterone as a downstream effector reduction comparable to that obtained with 50 mg
of some deleterious angiotensin II effects, and the growing eplerenone twice daily (the highest approved dose). The
awareness of the role of aldosteronism in resistant occurrence of adverse events and hyperkalemia was low
hypertension,13,14 have promoted the use of aldosterone and comparable in all active treatment groups.25 Despite
antagonists in patients with hypertension. The cur- the short half-life of LCI 699 (about 4 h), and the fact that
rently available aldosterone antagonists, spirono­lactone more detailed data on its effect on blood pressure, such
and eplerenone, act on the mineralocorticoid receptor. as trough to peak ratio, need to be published, these data
Their blood-pressure-lowering effects are comparable suggest that this drug might be suitable for once-daily
in hypertensive patients with and without increased dosing. As once-daily dosing is associated with improved
aldosterone levels,15–18 and both these agents seem to compliance with therapy,26 this feature might repre-
reduce mortality in a blood-pressure-independent sent an additional advantage over eplerenone, which is
manner in patients with heart failure.19–22 Although the administered twice daily at the highest approved dose.
antihypertensive effect is somewhat greater, milligram for However, aldosterone synthase inhibitors would not
milligram, for spironolactone than eplerenone,16 spirono­ prevent epithelial adverse effects, such as sodium reten-
lactone is associated with an increased rate of proges- tion and potassium excretion leading to hypertension,
terone-dependent and testosterone-dependent adverse or nonepithelial adverse effects, such as down­regulation
effects, mainly gynecomastia and breast tenderness.23 of nitric oxide synthase and promotion of inflamma-
Inhibition of aldosterone synthase should prevent tion, proliferation and fibrosis. These adverse effects
the reactive increase in aldosterone levels that occurs are mediated by cortisol, which in an altered redox state
in response to aldosterone antagonists, which triggers might act on the mineralocorticoid receptor.27 Data from
the undesired genomic, mineralocorticoid receptor- the phase II studies showed that LCI 699 did not affect
dependent effects (such as sodium/potassium exchanger baseline morning cortisol levels but did suppress adreno­
or sodium/hydrogen exchanger activation) and nonge- corticotropic hormone-stimulated release of cortisol in
nomic, mineralocorticoid receptor-independent effects ~20% of patients, probably owing to partial inhibition of
(such as phospholipase C and JNK kinase activation) of 11β-hydroxylase, which catalyzes the final step of cortisol
these agents, leading to inflammation, hypertrophy and synthesis.24,25 Thus, these findings raise the question of
fibrosis.2 LCI 699 could represent a first-in-class aldo- whether this suppressive effect might interfere with a clin-
sterone synthase inhibitor. Initial results in 14 patients ically useful response to stress (such as in acute injury)
with primary aldosteronism showed that twice-daily and compromise the safety of LCI 699, which could
administration of 0.5 mg or 1.0 mg of LCI 699 lowered lead to suspension of its clinical development. These
24 h ambulatory systolic blood pressure and supine concerns suggest that aldosterone synthase inhibitors
plasma aldosterone concentrations after 4 weeks.24 In a with greater specificity than LCI 699, such as SPP 2745,

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Table 1 | Compounds* newly approved or in clinical trials for the treatment of hypertension
Agent Mechanism of action Status
Azilsartan medoxomil AT1R blocker with peroxisome proliferator-activated Approved in 2011 by EMA and FDA
receptor γ activity
LCI 699 Aldosterone synthase inhibitor Phase II
LCZ 696 Dual AT1R blocker and neutral endopeptidase inhibitor Phase II (phase III for heart failure)
PS 433540 Dual AT1R and endothelin A receptor blocker Phase II
Daglutril Dual endothelin-converting enzyme and neutral Phase III
endopeptidase inhibitor
PL 3994 Natriuretic peptide receptor agonist Phase II (also phase II for
congestive heart failure)
AR 9281 Soluble epoxide hydrolase inhibitor Phase II (also phase II for diabetes
mellitus type 2)
Lercandipine, modified release Calcium-channel antagonist Phase II
Clonidine, controlled release Centrally acting α2-adrenergic agonist Phase III
*Only compounds approved by the FDA in 2010–20113,4 or listed as clinically investigated by the Pharmaceutical Research and Manufacturers of America
website5 on 1 December 2011 are included. Abbreviation: AT1R, angiotensin II type 1 receptor; EMA, European Medicines Agency.

could be useful as antihypertensive agents. However, experienced the largest blood-pressure-reducing effect,
the development of SPP 2745 was stopped following a which suggested synergism between NPRA agonism and
company merger, despite previous promising reports on ACE blockade.38
its specificity and cardioprotective, reno­protective, and
vasculoprotective effects. Further studies are needed to Soluble epoxide hydrolase inhibitors
demonstrate whether aldosterone synthase inhibitors Soluble epoxide hydrolase was identified as a novel
can deliver blood-pressure-independent, organ-protec- therapeutic target for blood-pressure control because its
tive effects comparable to those of mineralocorticoid inhibition (by a derivate of urea) had a blood-pressure-
receptor antagonists. lowering effect in spontaneously hypertensive rats, which
In addition to the specific aldosterone antagonists, have angiotensin-II-induced hypertension,39 but not in
some calcium-channel blockers can block mineralo­ normotensive Wistar rats.40 Inhibition of this enzyme
corticoid receptors28–30 or inhibit aldosterone synthe- also had antiproliferative effects.41 AR 9281 is the first
sis.31–33 These early data suggest that nonsteroid agents soluble epoxide hydrolase inhibitor that has advanced to
with double or triple actions on calcium channels, clinical trials. This agent is lipophilic, it can be adminis­
mineralo­corticoid receptors, and aldosterone synthase tered orally, and it lowered blood pressure, improved vas-
could potentially be developed.6 cular function, and reduced renal damage in rats with
angiotensin-II-induced hypertension.42–43 By contrast,
Natriuretic peptide receptor A agonists AR 9281 did not cause any blood-pressure-lowering
The endogenous factors atrial natriuretic peptide and effects in healthy human volunteers, although it inhibited
brain natriuretic peptide already serve as important soluble epoxide hydrolase and was well tolerated in an
markers of cardiovascular risk. These proteins have 8-day, dose-ranging study of single-dose and multiple-
natriuretic, vasorelaxant, and antiproliferative effects; dose treatment. 44 Nevertheless, elevated activity of
the pathways responsible for their action include NPRA soluble epoxide hydrolase was observed in patients
stimulation and guanylyl cyclase activation, with sub- with hypertension and diabetes mellitus,44 outlining the
sequent accumulation of cyclic GMP, which has puta- possible role of AR 9281 in these indications.
tive beneficial effects in hypertension, heart failure,
nephro­sclerosis, and stroke.34 Knockdown or knockout Angiotensin II type 2 receptor agonists
of NPRA results in reduced formation of cyclic GMP and Our research group identified AT2R as a possible thera-
increased blood pressure,35 whereas administration of peutic target for hypertension treatment.2 Stimulation
atrial natriuretic peptide elicits endothelium-dependent of AT2R opposes many aspects of AT1R stimulation
vasorelaxation.36 The NPRA antagonist PL 3994 is cur- by mediating vasodilatory, antiproliferative, and anti-
rently in a clinical phase of investigation in patients with inflammatory effects.45 The nonpeptide AT2R agonist
heart failure and hypertension.5 In phase I trials, PL 3994 compound 2146 has been used to investigate the direct
dose-dependently increased cyclic GMP levels, reduced effects of pharmacological AT2R stimulation. This
blood pressure, and induced natriuresis on the day fol- compound improved myocardial function indepen-
lowing treatment in healthy volunteers.37 Similar results dently of blood pressure after myocardial infarction in
(an increase in cyclic GMP and a reduction in blood normotensive Wistar rats,47 and suppressed inflamma-
pressure) were shown in a phase IIa study in patients tion and NF‑κB activity in primary murine and human
with adequately controlled essential hyper­tension.38 dermal fibroblasts.48 Despite this evidence of the cardio­
In this study, patients treated with ACE inhibitors protective potential of compound 21, the usefulness of

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Table 2 | Combinations* newly approved or in clinical trials for the treatment of hypertension
Combination Mechanism of action Status
Olmesartan, amlodipine, and AT1R antagonist, calcium-channel blocker, FDA and German‡ approval in 2010
hydrochlorothiazide and diuretic
Aliskiren, amlodipine, and Renin inhibitor, calcium-channel blocker, FDA approved in 2010, EMA approved
hydrochlorothiazide and diuretic in 2011
Aliskiren and amlodipine Renin inhibitor and calcium-channel blocker FDA approved in 2010, EMA approved
in 2011
Azilsartan medoxomil and chlortalidone AT1R antagonist and diuretic Preregistration
Candesartan cilexetil and nifedipine AT1R antagonist and calcium-channel blocker Phase II
*Only combinations approved by the FDA in 2010–20113,4 or listed as clinically investigated by the Pharmaceutical Research and Manufacturers of America 5 on
1 December 2011 are included. ‡Approval via the European decentralized procedure. Abbreviation: AT1R, angiotensin II type 1 receptor; EMA, European
Medicines Agency.

AT2R stimulation as a treatment for arterial hypertension (valsartan) in a phase II, randomized, double-blind,
was not clearly established by these studies. However, the placebo-controlled, and active-treatment-controlled
results of chronic treatment with compound 21 in two clinical trial in patients with mild-to-moderate essen-
different animal models of hypertension were reported tial hypertension.54 After 8 weeks of treatment, the two
during 2011. In stroke-prone spontaneously hyperten- highest doses of LCZ 696 (200 mg and 400 mg) achieved
sive rats, 6 weeks of treatment with compound 21, alone a larger reduction in sitting systolic and diastolic blood
or in combination with an AT1R blocker (losartan), pressures than was achieved using comparable doses
resulted in improved vascular stiffness and reduced col- of valsartan (160 mg and 320 mg). The 400 mg dose of
lagen concentration in the aorta and myocardium. The LCZ 696 also resulted in superior blood-pressure control
combination treatment also improved endothelium- and pulse-pressure reduction compared with valsartan.
dependent relaxation of resistance mesenteric arteries.49 In contrast to the results of trials of dual ACE and neutral
In rats with L‑NAME-induced hypertension, caused by endo­peptidase inhibitors, no angioedema was reported
nitric oxide synthase inhibition, compound 21 alone or in this study.54 With these encouraging data, LCZ 696 is
in combination with olmesartan reduced pulse wave now the most promising dual AT1R and neutral endo-
velocity. Moreover, only the combination treatment peptidase inhibitor in clinical trials for the treatment of
completely prevented collagen accumulation in the hyper­tension, as the development of the dual AT1R and
aorta, which resulted in a profound reduction of aortic neutral endopeptidase antagonist VNP 489 seems to be
stiffness.50 Most interestingly, the effects of AT2R stimu- halted (no novel data on VNP 489 have been reported in
lation in both these studies seemed to be independent the past 2 years).
of the changes in blood pressure, suggesting that com-
binations of this agent with antihypertensive treatment AT1R and endothelin A receptor blockade
might lead to vasculoprotective effects even beyond the Endothelin is one of the most-potent vasoconstrictors,
blood-pressure-reducing effect. and also has prominent roles in fibrogenesis, inflam-
mation, oxidative stress, atherosclerosis, salt and water
Dual inhibitors homeostasis, and pulmonary hypertension.55–57 Several
AT1R blockade and vasopeptidase inhibition endothelin receptor antagonists have been investi-
Neutral endopeptidase is a metallopeptidase that metabo­ gated for the treatment of hypertension. The selective
lizes various vasodilatory and vasoconstrictive sub- endothelin A antagonist darusentan achieved promis-
stances, leading to variable effects on blood pressure.51 ing blood-pressure reductions in patients with resis-
However, if this enzyme is inhibited in the presence of tant hypertension in the DAR‑311 (DORADO) trial,58
concomitant vasoconstrictor blockade, the effect of and a larger reduction in mean 24 h systolic and dia-
reduced degradation of vasodilatory substrates might stolic blood pressure than either placebo or the sym-
outweigh that of vasoconstrictive substrates, leading to patholytic antihypertensive agent guanfacine in the
a net vasodilatory effect. DAR‑312 (DORADO-AC) trial.59 However, adverse
The OCTAVE and OVERTURE trials of the dual effects—salt and water retention and the development
ACE–neutral endopeptidase inhibitor omaptrilat were of peripheral edema—limit the tolerability of endo­
encouraging in terms of efficacy in hypertension and thelin A receptor blockers58–61 and probably contributed
heart failure. However, they highlighted an increased to the decision to put development of darusentan on
incidence of angioedema after treatment with dual ACE hold. Nevertheless, these findings raise the question of
and neutral endopeptidase inhibitors compared with whether dual-specificity AT1R and endothelin A recep-
the ACE inhibitor enalapril.52,53 Consequently, atten- tor antagonists (such as PS 433540, which is currently
tion has shifted to dual AT1R and neutral endopeptidase under clinical investigation as a treatment for hyper­
antagonism. The putative first-in-class dual AT1R and tension) could be more effective and better tolerated than
neutral endopeptidase antagonist LCZ 696 achieved a specific endothelin A receptor blockers. In a phase IIb,
blood-pressure reduction comparable to an AT1R blocker randomized, double-blind, placebo-controlled, and

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REVIEWS

active-treatment-controlled trial in patients with stage peri­p heral edema, caused by the calcium-channel
1–2 hypertension, PS 433540 (at doses of 200 mg, 400 mg, blocker, in patients receiving the combination treatment
and 800 mg) reduced systolic and diastolic blood pres- compared with patients receiving amlodipine mono-
sures more effectively than placebo, with the highest dose therapy.72 Similarly, a meta-analysis of 43 randomized,
achieving a greater reduction than the AT1R blocker irbe- controlled trials showed that addition of the diuretic
sartan. In addition, compared with irbesartan, all doses hydro­chlorothiazide to AT1R antagonists resulted in
of PS 433540 were associated with improved rates of enhanced blood-pressure reduction in hypertensive
blood-pressure control (<140/90 mmHg) at 12 weeks.62 patients;73 moreover, AT1R-blockade-induced potas-
Although these results were encouraging, they have not sium retention might also counterbalance the potassium
been published in a peer-reviewed journal, and clinical losses caused by diuretic administration.74
development of this agent has been suspended until a Interest in the development of combination thera-
commercial partner is found.63 pies is increasing because of their superior efficacy
and the potential to allow challenging blood-pressure
Vasopeptidase and ECE inhibition targets to be met. In addition, patients prefer to take
Endothelin is produced by another metallopeptidase, as few pills as possible,26 and adherence to fixed-dose
ECE. The dual ECE and neutral endopeptidase inhibitor combinations of two agents given as a single pill is
daglutril (SLV 306, a prodrug for the active compound better than adherence to free combinations of the same
KC 12615) reduced both proteinuria and glomerulo­ agents.75 Since 2000, 13 new fixed-dose combinations,
sclerosis in rats with streptozotocin-induced diabetes to including three triple therapies, have been approved for
an extent comparable to the ACE inhibitor captopril,64 an treatment of hyper­tension. Three of these agents, one
effect previously not observed with sole ECE inhibition.65 double therapy and two triple therapies, were approved
Although daglutril reduced pulmonary and right atrial in 2010–2011 (Table 2).
pressure in patients with congestive heart failure,66 this The renin inhibitor aliskiren was approved as a mono-
study was published in 2004 and more-recent data on therapy in 2007. Three combination therapies involving
this substance are not available. However, some other this agent are now available: aliskiren plus hydrochloro-
dual ECE and neutral endopeptidase inhibitors, such thiazide (approved in 2008), aliskiren plus amlodipine,
as SLV 338, are in preclinical pipelines. In stroke-prone, and aliskiren plus amlodipine plus hydrochlorothiazide
spontaneously hypertensive rats, SLV 338 treatment was (both approved in 2010). The aliskiren plus amlodipine
well tolerated and associated with improved survival combination achieved greater blood-pressure reduction
as well as a significantly lowered incidence of stroke. than either component alone in patients with mild-to-
However, the treatment did not have a significant effect severe hypertension after 8 weeks of treatment.76
on blood pressure.67 The approval of aliskiren (300 mg) in a fixed-dose
triple combination therapy with amlodipine (10 mg)
Combination therapies and hydrochlorothiazide (25 mg) was on the basis of the
Currently a single pharmacologic agent is sufficient to results of a double-blind, active-treatment-controlled
achieve adequate blood-pressure control in only approxi- trial in patients with moderate-to-severe hypertension.
mately one-third of patients with hypertension; another These data showed that the triple combination achieved
one-third will need two drugs, and the rest require at a greater mean blood-pressure reduction than three two-
least three agents.68 These requirements are reflected drug combinations: aliskiren plus hydro­chlorothiazide
in the current European guidelines, which recommend (9.9/6.3 mmHg), amlodipine plus hydrochlorothia-
the use of a combination of at least two antihypertensive zide (7.2/3.6 mmHg), and aliskiren plus amlodipine
drugs in patients with mild-to-severe (grade ≥2) hyper- (6.6/2.6 mmHg).77 Although none of these combinations
tension.69 Trials of antihypertensive therapy in patients included an AT1R antagonist or an ACE inhibitor, such
with heart failure have demonstrated that mortality can a combination was investigated in the ALTITUDE trial,
be reduced progressively by the inclusion of additional which was designed to determine whether the addition
antihypertensive agents in the treatment regimen; mor- of aliskiren (300 mg once daily) to conventional treat-
tality was progressively reduced in the following trials: ment (including AT1R antagonist or an ACE inhibitor)
SOLVD (diuretic and ACE inhibitor), CIBIS II and of patients with type 2 diabetes, reduced cardiovascu-
RALES (diuretic, ACE inhibitor, and either β‑blocker or lar and renal morbidity and mortality compared with
spironolactone), and CHARM (diuretic, ACE inhibitor, placebo.78 However, this trial was halted prematurely
β‑blocker, and ARB).70 because of an increase in adverse events and no appar-
Combination therapy provides superior blood- ent benefits among patients randomly assigned to
pressure reduction because each agent typically blocks aliskiren.79 These data suggest that the combination of
the counter-regulatory system activity triggered by the aliskiren with an AT1R antagonist or an ACE inhibitor
other 71 and might also attenuate its adverse effects. For might be dangerous and should not be used.
example, the combination of a calcium-channel blocker The results on the efficacy of aliskiren in dual or triple
(amlodipine) with an AT1R antagonist (valsartan) was combination therapies for hypertension are in line with
more effective in reducing blood pressure than either previous data on other RAAS blockers in combina-
drug alone,72 and the AT1R blockade-induced dilatation tion therapies. For example, a study that evaluated the
at the venous capillary side reduced the occurrence of efficacy of combinations of valsartan, amlodipine, and

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 FOCUS ON HYPERTENSION

hydrochlorothiazide in patients with hypertension (mean

sitting diastolic blood pressure >100 mmHg) showed
that the triple drug combination lowered blood pres-
sure by 40/25 mmHg. This reduction was significantly
greater than that achieved by treatment with two-drug
combinations of valsartan and hydrochlorothiazide, val-
sartan and amlodipine, or amlodipine and hydrochloro-
thiazide, which lowered blood pressure by 32/20 mmHg,
34/22 mmHg, and 31/19 mmHg, respectively.80
A triple combination of olmesartan (40 mg), amlo-
dipine (10 mg), and hydrochlorothiazide (25 mg) was
approved in 2010 on the basis of the TRINITY results
in patients with hypertension.77 The triple combina-
tion treatment lowered blood pressure by 37/22 mmHg,
which was superior to the blood-pressure reductions in
the double-drug arms (30/17 mmHg with olmesartan
and hydrochlorothiazide, 30/18 mmHg with olmesar-
tan and amlodipine, and 28/15 mmHg with amlodipine
and hydrochlorothiazide).77
To date, only triple combinations that include amlo- Figure 1 | Schematic representation of renal sympathetic denervation. An ablation
dipine as the calcium-channel blocker and hydro­ catheter is guided into each main renal artery. On activation, the catheter
chlorothiazide as the diuretic have been investigated. generates a spherical region of increased temperature that burns an area
The available data from the ACCOMPLISH81 trial and approximately one-quarter of the circumference of the artery. Catheter rotation,
comparisons of data from the double-agent arms of with up to six burns, provides a full circumferential ablation and effective
other triple therapy trials suggest that combinations of destruction of the sympathetic nerve fibers (yellow) surrounding the renal artery.
a RAAS blocker and a calcium-channel blocker might Permission obtained from Oxford University Press, © Krum, H. et al. Novel
procedure- and device-based strategies in the management of systemic
have superior efficacy to combinations that include a
hypertension. Eur. Heart J. 32, 537–544 (2011).
diuretic. However, this finding might be an artifact result-
ing from the choice of hydrochlorothiazide (a relatively
weak diuretic), and the use of relatively low doses of this 106 patients with treatment-resistant hypertension.
agent. The efficacy data for other fixed-dose dual thera- At 6 months after the procedure, office blood pres-
pies being investigated in clinical studies are, therefore, sure decreased significantly, by 32 ± 23/12 ± 11 mmHg,
highly anticipated, as chlorthalidone82 and nifedipine83 in the renal denervation (plus ongoing therapy) group
are being used as the diuretic and calcium-channel (52 patients), whereas it did not change from baseline
blocker, respectively. in the control group (ongoing therapy only, 54 patients).
Additionally, 84% of the patients who underwent renal
Nonpharmacological therapies denervation had a reduction in systolic blood pressure
Renal sympathetic denervation of ≥10 mmHg, compared with 35% of patients in the
Although renal sympathectomy was an early method control group (P <0.0001). For some patients, the data
used to reduce blood pressure, it was abandoned after from a 24‑h ambulatory blood-pressure measurement
effective pharmacological therapies were introduced. at 6 months were available: in the renal denervation
However, the development of novel, minimally inva- group (20 patients) a significant decrease from baseline
sive, catheter-based approaches and the need to develop was observed for both the mean systolic and diastolic
effective therapies for treatment-resistant hyperten- blood pressure (by 11 ± 15/7 ± 11 mmHg), while no
sion have revived the strategy. The current procedure significant change was observed in the control group
involves percutaneous radiofrequency ablation of sym- (25 patients). No serious procedure-related or device-
pathetic nerve fibers surrounding the renal arteries, via related complications occurred.87 A follow-up study of
an intra-arterial catheter (Figure 1). 84,85 This method patients who underwent renal nerve ablation showed
of renal denervation was initially evaluated in a cohort that postprocedure blood pressures remained below
study of 45 patients with treatment-resistant hyper­ baseline, by 23/11 mmHg after 12 months (n = 64) and
tension. Renal epinephrine spillover decreased by 47% by 32/14 mmHg (n = 18) after 24 months, suggesting a
and office blood pressure was reduced by 14/10 mmHg, persistent effect of the procedure.88
21/10 mmHg, 22/11 mmHg, and 27/17 mmHg at 1, 3, 6, Although these results87,88 are encouraging, further
and 12 months, respectively, after the procedure. Adverse studies are required to clarify several factors that might
events included one intraprocedural renal-artery dissec- affect the efficacy of renal denervation, including
tion before ablation, and one femoral-artery aneurysm patient eligibility criteria, the need for continued drug
without further complications.86 treatment, the number of drugs required to keep blood
The safety and efficacy of catheter-based renal dener- pressure controlled, and the potential for achieving
vation for blood-pressure reduction was investigated long-term blood-pressure reduction in view of the loss
further in the Symplicity HTN‑2 Trial,87 which included of renal sympathetic activity and the possibility of renal

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© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS

sympathectomy.93 However, further data are needed to

show whether this approach will be better tolerated by
patients than radiofrequency ablation, and to determine
whether the beneficial effect will be as durable.
BP
Baroreceptor activation
Baroreflex activation therapy (BAT) is a device-based
approach to treating hypertension that has been inten-
sively investigated. The BAT device consists of an
implantable pulse generator that activates the carotid
Electrode sinus via an electrical signal, delivered by bilateral leads.
The leads are implanted during open surgery and the
electrodes are positioned at the areas of greatest response
in the carotid sinus. Stimulation of the sinus by the BAT
device supplies the blood pressure control centers with
false information of increased blood pressure, leading to
reflexive blood pressure lowering (Figure 2).94
Data from the DEBuT-HT trial,95 which assessed BAT
in 45 patients with hypertension, showed that 72% of
BAT device patients had a reduction in systolic blood pressure of at
BP
least 30 mmHg after 4 years of treatment (mean reduc-
tion 53 ± 9 mmHg, P <0.001). The mean reduction in
diastolic blood pressure at 4 years was 30 ± 6 mmHg
(P <0.001) and the drop in heart rate averaged 5 ± 2 bpm
(P = 0.02) against baseline. The average number of anti-
hypertensive medications used decreased from 5.0 at
BP baseline to 3.4 over the same time period.96
A large (n = 265) phase III, double-blind, randomized,
prospective, multicenter, placebo-controlled study of the
same device confirmed the efficacy and safety of BAT in
patients with resistant hypertension. The results showed
that target systolic blood-pressure values of <140 mmHg
were achieved in 42% of patients who received 6 months
of BAT, compared with 24% of patients who were
Figure 2 | Schematic representation of baroreflex activation therapy. The BAT implanted with the BAT device but did not receive
device consists of an implantable pulse generator, bilateral carotid sinus leads stimulation during this period. A mean systolic blood-
delivering stimulation to the area of greatest response, and an external
programmable device for noninvasive control of the pulse generator. Stimulation of pressure reduction (from preimplant values) of 26 mmHg
the carotid sinus by this device supplies false information indicating hypertension in patients who received BAT and 17 mmHg in patients
to the blood pressure control centers of the central nervous system, leading to who did not receive BAT (device implanted but not
reflexive blood pressure lowering. Abbreviation: BAT, baroreflex activation therapy; activated) was seen in the same time period. The mean
BP, signals resulting in decreased blood pressure; BP, false signal indicating
increased blood pressure. Permission obtained from Nature Publishing Group © blood-pressure decrease and proportion of patients who
Mearns, B. M. Nat. Rev. Cardiol. 8, 540 (2011). met the <140 mmHg blood-pressure goal had somewhat
increased 12 months after BAT therapy, to 35mmHg and
53%, respectively.97 Although these data were encourag-
re-innervation. Initial data from animal experiments ing, and predefined efficacy, BAT safety, and device
suggest that renal re-innervation might occur; in rats re- safety end points were met, the study did not meet the
innervation was complete and functional at 8 weeks after predefined procedural safety criteria of no implantation-
renal denervation,89 whereas in dogs functional re-inner- procedure-related adverse effects in 82% of patients, as
vation was complete 12–16 months after the procedure.90 only 75% of patients did not experi­ence adverse effects
However, although it is evident that human kidney such as transient or permanent nerve injury, general
undergoes re-innervation after renal transplantation, 91 surgical complications, and surgical wound infection.
this re-innervation might be nonfunctional 92 and the Several technical improvements are, therefore, likely to
extent to which re-innervation could affect the outcome be required—most importantly device size reduction, and
of renal denervation in humans remains unclear. As the the development of a unilateral device with comparable
blood-pressure-lowering effect of the procedure per- efficacy to the bilateral version used in these studies.95
sists 24 months after denervation,88 a longer follow-up To address these concerns, a smaller, second-generation
is required to answer this question and increase our unilateral BAT device was introduced in 2011. This device
know­ledge of re-innervation in human kidney. has been reported to offer improved procedural safety
Chemical denervation with locally applied vin- and comparable blood-pressure-reducing efficacy to the
cristine has also been suggested as a method of renal bilateral BAT device.98

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© 2012 Macmillan Publishers Limited. All rights reserved
 FOCUS ON HYPERTENSION

Conclusions have also advanced considerably and, as the technologies

Although development of new medications and treat- progress, they might represent a strategy to overcome the
ment strategies for hypertension is still required, the problem of treatment-resistant hypertension.
investigation of novel therapeutic compounds for this
indication (especially those with novel targets) seems Review criteria
to be losing momentum. Nevertheless, clinicians can Drugs approved in 2010–2011 were identified using the
remain optimistic that new antihypertensive drugs with CenterWatch and FDA databases, and those in clinical
novel mechanisms of action will be approved in the next development were identified using the PhRMA database.
10 years. The aldosterone synthase inhibitors currently Two nonpharmacological treatments, on which data were
presented in 2010–2011, were also included. PubMed
in drug-development pipelines seem to show particular
was searched using the following keywords: “azilsartan”,
promise, although problems of specificity and funding “LCI 699”, “PL 3994”, “LCZ 696”, “AR 9281”,
need to be addressed, and the development of novel “PS 433540”, “daglutril”, “compound 21”, “renal
molecules with dual activity (probably including AT1R denervation” and “baroreceptor activation therapy”, alone
antagonism) is likely to continue. However, approvals for and in combination. Additional information was retrieved
antihypertensive therapies in the near future will probably from the EBSCO database, Google Scholar, and Google
be dominated by new fixed-dose combinations, includ- searches. The reference lists of key review articles
ing a broader and more variable range of triple therapies. identified during these searches were also checked for
additional relevant publications.
Device-based approaches to antihypertensive treatment

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