European Heart Journal - Cardiovascular Pharmacotherapy (2020) 6, 188–193 REVIEW

doi:10.1093/ehjcvp/pvz057

Hypertension

Resistant hypertension: new insights and

therapeutic perspectives
Luis M. Ruilope 1,2,3,4*, Elena Rodrı́guez-Sánchez1, José Alberto Navarro-Garcı́a1,
Julian Segura1, Alberto Órtiz5, Alejandro Lucia6, and Gema Ruiz-Hurtado 1,2*

Downloaded from https://academic.oup.com/ehjcvp/article/6/3/188/5584256 by guest on 30 May 2022

1
Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research iþ12, Hospital Universitario, 12 de Octubre, Madrid, Spain; 2Hospital Universitario, 12 de
Octubre, Madrid, CIBER-CV, Spain; 3Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; 4Universidad
Europea de Madrid, Madrid, Spain; 5IIS-Fundacion Jimenez Diaz UAM and School of Medicine, UAM, Madrid, Spain; and 6Faculty of Sports Sciences, Universidad Europea de
Madrid, Madrid, Spain

Received 3 July 2019; revised 7 August 2019; editorial decision 25 September 2019; accepted 4 October 2019; online publish-ahead-of-print 9 October 2019

Resistant hypertension (RH) is a concept that currently goes beyond the classical definition of blood pressure >_140/90 mmHg in subjects
receiving three or more drugs of different classes at maximally tolerated doses. Here, we review the clinical relevance of RH and the dif-
ferent types of RH-associated phenotypes, namely refractory hypertension, controlled resistant hypertension, and masked uncontrolled
hypertension. We also discuss current drug strategies and future treatments for these high-risk phenotypes.
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Keywords Uncontrolled hypertension • Resistant hypertension • Refractory hypertension • Controlled resistant

hypertension • Masked uncontrolled resistant hypertension

.. be considered as having controlled RH (cRH). Second, a phenotype

Introduction ..
.. different from ‘classical’ RH has been identified—termed ‘refractory
..
Resistant hypertension (RH) has been traditionally defined by clinic .. hypertension’ (RfH)—that includes those patients who remain un-
(or ‘office’) blood pressure (BP) >_140/90 mmHg in patients receiving .. controlled despite receiving at least five antihypertensive drugs
..
at least three antihypertensive drugs, one of which is a diuretic, at .. including chlorthalidone and spironolactone. The mechanisms under-
maximally tolerated doses. The new European Society of Cardiology/ .. lying RH and RfH apparently differ, with persistent excess intravascu-
..
European Society of Hypertension (ESC/ESH) guidelines1 maintain .. lar fluid retention being the main trigger for RH but not for RfH.
this definition of RH whereas the American College of Cardiology/
.. Another aspect of great interest, in our opinion, is that guidelines
..
American Heart Association (ACC/AHA)2 consider RH as office .. have not considered one of the most important risk phenotypes
BP > 130/80 mmHg in patients taking 3þ antihypertensive agents,
.. observed in ambulatory BP, which is masked uncontrolled hyperten-
..
including a renin–angiotensin system (RAS) inhibitor, a calcium chan- .. sion (MUCH)—a condition found in some patients treated for
nel blocker (CCB), and a diuretic at maximally tolerated doses.3
.. hypertension with apparently well-controlled BP in the office, yet
..
The identification of another hypertensive phenotype, pseudo-RH, is .. with high out-of-office BP.4 Indeed, according to our recent study
..
currently performed by discarding the main triggers for this condi- .. demonstrating that the risk of death associated with MUCH is the
tion: poor patient adherence, a white-coat phenomenon, poor office .. second highest after masked hypertension,5,6 Masked uncontrolled
..
BP measurement technique, marked brachial artery calcification, and .. hypertension should be screened for in patients with apparent cRH
clinical inertia.1 After accounting for pseudo-RH and secondary forms .. (this ‘combined’ phenotype is herein referred to as ‘RH-MUCH’)
..
of hypertension, the prevalence of RH is currently estimated to be .. because the associated increase in risk requires more aggressive
less than 10% in patients under treatment for hypertension.1 .. therapeutic approaches.
..
Interestingly, the recent ACC/AHA guidelines2 have introduced two .. This article is an in-depth review and update of the different
other concepts when considering RH. First, patients receiving at least
.. RH-associated phenotypes: rfRH, cRH, and MUCH (see Box 1 for
..
four antihypertensive drugs but achieving an adequate BP control can . definitions). We also review the different aspects of pharmacological

* Corresponding author. Tel: þ34913908001, Email: ruilope@icloud.com (L.M.R.); Email: gemaruiz@h12o.es (G.R.-H.)
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
New insights and therapeutic perspectives of resistant hypertension 189

Box 1 Definition of the different resistant hypertension-associated phenotypes

• RH (resistant hypertension): patients with elevated office blood pressure and 24-h blood pressure under treatment with three drugs, one
being a diuretic.
• rfRH (refractory RH): patients with elevated office blood pressure while on treatment with five or more drugs.
• cRH (controlled RH): patients receiving at least four antihypertensive drugs and achieving an adequate blood pressure control in the
office.
• MUCH (masked uncontrolled hypertension): patients receiving at least four antihypertensive drugs and achieving an adequate blood pres-
sure control in the office, but with elevated out-of-office blood pressure.

..
therapy of these phenotypes characterized by difficult-to-control .. number of pills taken daily. In our opinion, if the effect of spironolac-
BP with a look into the future. .. tone is not positive, withdrawal of this drug must be considered
..

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.. owing to its side effects.
The problem of measuring medication .. Adherence to lifestyle and medication is the most important factor
..
adherence for the recognition of .. to achieve adequate BP control. Confirmation of adherence is
.. required for the correct diagnosis of RH, RfH, and RH-MUCH
resistant hypertension, refractory ..
.. according to new guidelines.1,2 The identification of patients with low
hypertension, and resistant .. adherence to medication is crucial to avoid unnecessary intensifica-
hypertension-masked uncontrolled ..
.. tion of treatment and requires the application of strategies to im-
hypertension ..
.. prove adherence.
The initial three antihypertensive drugs to be used in most patients .. ESC/ESH guidelines recommend several methods to assess adher-
..
with hypertension according to both new guidelines are a RAS inhibi- .. ence to treatment.1 The most effective approach, albeit difficult to
tor, a CCB, and a diuretic. The drug number four for those presenting .. implement in routine clinical practice, consists of quantifying antihy-
..
with RH (as confirmed by ambulatory BP assessment) is the min- .. pertensive drugs or their metabolites in urine and blood. Of note,
eralocorticoid receptor antagonist (MRA) spironolactone, followed, .. this method has been shown to be cost-effective.7 However, patients
..
if needed, by a beta-blocker such as bisoprolol (drug number five) .. must be blind to this method to avoid having non-adherent patients
and an alpha-blocker such as doxazosin (drug number six) (Figure 1). .. taking the pills only before drug/metabolite testing. This would be fol-
..
A combination of these with the alpha-2 selective agonist clonidine is .. lowed by pill counting and prescription refills. Finally, patient educa-
another option. The use of a triple fixed-combination of drugs 1–3 .. tion and self-monitoring using home BP measurement is
..
(diuretic-RAS blocker-CCB) allows for a reduction in the total . recommended, and telemonitoring and smartphone applications

Figure 1 Diagnostic and therapeutic approach to resistant hypertension and its associated phenotypes. Patients with controlled hypertension and
especially those with controlled resistant hypertension (cRH) should be screened for the presence of masked uncontrolled hypertension (MUCH)
or resistant hypertension (RH)-masked uncontrolled hypertension phenotypes, as they imply a very high cardiovascular risk. In contrast, patients
with uncontrolled hypertension should be screened for pseudo-resistant hypertension (PRH). Antihypertensive treatment should follow the treat-
ment upper line from diuretic/renin-angiotensin system (RAS) inhibitor/calcium channel blocker (CCB) to clonidine. Initiation of statin treatment
should be considered since the initiation of antihypertensive fourth-line treatment with a mineralocorticoid receptor antagonist (MRA) or diuretic
reinforcement. ABPM, ambulatory blood pressure monitoring; RfH, refractory hypertension.
190
..
have proven useful for increasing medical adherence. As a last resort,
patients might be invited to bring their medication to the office,
where BP would be recorded using an ambulatory device every
15 min for a total of 3 h after taking the medication in the presence of
a nurse: a significant reduction in BP during this time frame indicates
that the patient is non-adherent out-of-office. Thereafter, any of the
aforementioned methods can be used to detect poor adherence.1
Finally, it is our opinion that the joint role of doctor and nurse
investing ‘adequate’ time in direct contact with patients is a key re-
quirement to confirm patient adherence.
Prevalence and pathophysiology
of resistant hypertension,
refractory hypertension,
controlled resistant hypertension
and resistant hypertension-
masked uncontrolled
hypertension
Prevalence
In the hypertensive population included in the Spanish Ambulatory
Blood Pressure Registry (N = 63 910),8–10 the reported prevalence
(using the thresholds set by the new ESC/ESH Guidelines1) was
12.2% (RH phenotype), 1.4% (RfH), and 2.6% (cRH). Regarding the
RH-MUCH phenotype in patients receiving 3þ drugs (total N = 11
963), the reported prevalence was 5.2% (for daytime), 10.7% (night-
time), and 7.2% (24 h). Thus, there is a relevant proportion of the
total hypertensive population for which appropriate pharmacological
and interventional strategies would need to be considered to reduce
the very high risk associated with these RH phenotypes.
Pathophysiology
Different mechanisms possibly related to relative aldosterone excess
in some patients are apparently implicated in the development and
progression of RH, RfH, and RH-MUCH. Chief among these are
increased blood volume and sympathetic activity, but the influence of
cortisol and pro-inflammatory factors should also be considered.11
An in-depth analysis of endocrine and haemodynamic changes in RH
and BP responses to spironolactone or amiloride was recently per-
formed as a substudy of the PATHWAY-2 trial,12 showing that RH is
commonly a salt-retaining state secondary to enhanced aldosterone
secretion. Pimenta et al. (2009) demonstrated that, in the absence of
changes in medication, a decrease in salt-intake to 4–6 g/day signifi-
cantly improved BP control.13 Spironolactone correction of excess
volume seems to be determinant to overcome treatment resistance.
In the PATHWAY-2 trial, the role of sympathetic activity in a smaller
percentage of patients was demonstrated by the good response to
bisoprolol and doxazosin.12 By comparison, the role of excess vol-
ume in RfH has been shown to be less important11,14 and increased
sympathetic output, rather than inadequate fluid retention, seems to
be the trigger for refractoriness in these patients.15 Also, when com-
pared with their RH peers, patients with RfH present with a more
marked cardiovascular disease (CVD) risk profile,9 higher BP levels
L.M. Ruilope et al.
.. and a two-fold higher risk for obstructive sleep apnoea or a more se-
.. vere manifestation of this condition.16 With respect to RH-MUCH,
..
.. adequate adherence to pharmacological treatment is mandatory to
.. diagnose this condition, as we have mentioned earlier. Otherwise,
..
.. hypertension would be masked hypertension, not MUCH.
.. Overactivity of the sympathetic system seems to be the main trigger
..
.. for both masked hypertension and MUCH,17 with the two conditions
..
.. associated with a markedly elevated risk of CVD events and all-cause
.. mortality.5,18 Consequently, patients with RfH might have similar or
..
.. even higher levels of CVD risk than their RH or RH-MUCH peers.
..
..
.. Lifestyle
.. A healthy lifestyle is undoubtedly an important coadjuvant to attain
..
.. adequate control of RH and other phenotypes.19 As mentioned, a de-
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.. crease in salt-intake to 4–6 g/day is important and, in fact, the benefit
..
.. of MRAs is based on counteracting the hypertensive effects of high
.. dietary sodium.20 Furthermore, regular aerobic exercise (e.g. brisk
..
.. walking) has proven to decrease both systolic and diastolic BP in
..
.. hypertensive patients21 and is broadly recommended by international
.. guidelines.1,2 The evidence supporting the benefits of physical exer-
..
.. cise is still scarce for patients with RH, but the few studies that have
.. been conducted report promising outcomes,22–24 and regular physic-
..
.. al activity is associated with a reduced risk for mortality and CVD
.. events in RH.19 Notably, even a single session of light- or moderate-
..
.. intensity aerobic exercise acutely reduces ambulatory BP in patients
.. with RH, with benefits persisting longer following light intensity.25
..
..
.. Pharmacological treatment
..
.. Spironolactone is the fourth drug added when a patient is not suffi-
..
.. ciently controlled with three drugs, with one being a diuretic. As was
.. shown in the PATHWAY-2 study,12 more than 50% of patients are
..
.. controlled with spironolactone, which is clearly superior to placebo,
.. bisoprolol, or doxazosin. If spironolactone is not tolerated, positive
..
.. results can be obtained with amiloride12 or eplerenone.3 The ab-
.. sence of response to MRAs could be due, at least partly, to obesity,
..
.. particularly abdominal obesity, which contributes to further increase
.. excess aldosterone,26 and also to the presence of the -344 C/T poly-
..
.. morphism in the aldosterone synthase-encoding gene (CYP11B2).27
..
.. New anti-obesity drugs such as the glucagon-like peptide-1 agonists
.. liraglutide and semaglutide28 need to be tested in RH.
..
.. When the response to an MRA is not satisfactory, diuretic treat-
.. ment reinforcement to achieve sequential nephron blockade (spir-
..
.. onolactone and furosemide) is superior to dual RAS blockade.29 Of
.. note, primary aldosteronism (with a reported prevalence in primary
..
.. care practice as high as 11.8%30) cannot be discarded without assess-
.. ing the BP response to even higher doses of spironolactone of 25–
..
.. 50 mg/day. Higher doses are needed to treat primary aldosteronism
.. and, if renal function and tolerability allow, an up-titration of the MRA
..
.. dose can be attempted. In our experience, non-responders to spir-
..
.. onolactone or individuals who are intolerant to this drug can benefit
.. from the addition of chlorthalidone and aliskiren (i.e. in 15 of 16
..
.. patients).31
.. The aforementioned good response to an MRA and diuretic re-
..
.. inforcement is observed in RH patients with excess volume, as clearly
.. shown in the PATHWAY-2 study.12 Failure to respond to volume-
..
. targeting therapies imposes the addition of drugs targeting
New insights and therapeutic perspectives of resistant hypertension
..
sympathetic over-activity, including bisoprolol, doxazosin or a com-
bination thereof, according to ESC/ESH guidelines.1 The presence of
a marked sympathetic activation and baroreflex dysfunction in true
RH, clearly above that detectable in arterial hypertension, has been
shown.17 These alterations cannot be corrected through a decrease
in volume and require targeting of the sympathetic system because
sympathetic over-activity promotes the failure of conventional anti-
hypertensive treatment.32 The addition of the fifth and successive
drugs takes us into the territory of RfH, where sympathetic inhibition
could lead to a better response. Indeed, the recent finding that cloni-
dine was not superior to spironolactone as the fourth drug in true
RH,33 and the lower percentage of control on bisoprolol and doxa-
zosin in PATHWAY-2,12 is worthy of mention and suggests that the
majority of patients in these two studies presented with an excess of
intravascular volume that counteracted the inhibitory effect of these
drugs on sympathetic activity. Hence, this hypothesis should be
addressed in future studies. Another important consideration in RH
treatment is the need to add a statin if not done before because of
the well-demonstrated efficacy of these drugs for preventing CVD
events shown in the TNT trial,34 which included patients with coron-
ary artery disease and LDL-cholesterol < 130 mg/dL.
Chronic kidney disease
An unresolved issue, however, is the care for RH patients with chron-
ic kidney disease (CKD), especially those at an advanced stage of this
condition [i.e. with an estimated glomerular filtration rate (eGFR) <
30 mL/min/1.73 m2 or on dialysis35]. Resistant hypertension is more
frequent in this patient population and its prevalence increases as
eGFR decreases. Also, patients with CKD are more frequently non-
adherent to treatment, and are prone to arterial rigidity, volume
overload, suboptimal responses to diuretics and sympathetic system
overactivity, or to treatment side effects such as hyperkalaemia, par-
ticularly if RAS blockade is combined with MRA blockers. Moreover,
when choosing a beta-blocker, a diminished kidney excretion of this
drug secondary to a low eGFR must be considered to prevent
drug accumulation. Lastly, these patients are routinely excluded from
clinical trials (e.g. the PATHWAY-2 study enrolled patients with
eGFR > 45 mL/min/1.73 m2).12
Finally, although the treatment approach for a patient with an RH-
MUCH phenotype is not yet defined in the literature, it seems logical
to start with an MRA, followed by diuretic reinforcement and sympa-
thetic blockade if excess volume fails to be corrected (given the
suggested overactivity of the sympathetic system in these patients).
A look into the future: is renal
denervation back on the table in
the management of arterial
hypertension?
The capacity of renal denervation (RDN) to diminish renal and sys-
temic sympathetic tone was demonstrated by Esler et al.36 and initial
trials in RH showed positive results.37,38 In contrast, the SYMPLICITY
HTN-3 trial,39 which was randomized, blinded, and sham-controlled,
showed no significant differences between RDN and sham.
However, the veracity of the trial data has been questioned.40 Renal
191
.. denervation continues to be explored in the Global SYMPLICITY
.. Registry,41 which has recruited several thousand patients in routine
..
.. clinical care conditions. Results from this registry support a positive
.. role of RDN in BP control. Furthermore, recent studies investigating
..
.. the role of RDN vs. sham intervention in patients off medication42,43
.. or on 1–3 drugs44 have provided the proof-of-principle for the effi-
..
.. cacy of RDN to lower BP. Further trials are ongoing which, if positive,
.. would confirm that RDN can be used to treat hypertension in the
..
.. absence of medication, and also in treated and uncontrolled hyper-
..
.. tension including patients with RH, RfH, or RH-MUCH phenotypes.
.. However, if RCTs fail to yield positive results, RDN will not be
..
.. recommended. Given the issues with current drug approaches
.. for RH in patients with CKD, RDN might be efficacious in this
..
.. population.35 Although patients with advanced CKD have been
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.. excluded from large trials, small exploratory studies suggest that
..
.. RDN is safe in CKD. The safety and efficacy of RDN should be
.. confirmed in larger sham-controlled studies.
..
.. The development of new drugs to treat RH is unlikely given the
..
.. issues of poor adherence, white-coat effect, suboptimal therapy and
.. the increased costs of any new drug.45 Moreover, the interest of
..
.. pharmaceutical companies should perhaps be limited to RfH, which
.. represents a low percentage of uncontrolled hypertensive patients.
..
..
..
..
.. Conclusions
..
.. Figure 1 shows a scheme of how to classify uncontrolled hypertension
..
.. and adequately treat each one of the phenotypes observed in clinical
.. practice. Spironolactone or other MRAs are the drugs of choice in
..
.. the fourth position, followed by a beta- (bisoprolol) and alpha- (dox-
.. azosin) blocker, and an alpha-2 selective agonist (clonidine). In
..
.. patients with cRH, ambulatory BP assessment should be mandatory
.. to screen for RH-MUCH. The role of RDN in RH remains an open
..
.. question. However, the assessment of the uncontrolled hypertensive
..
.. patient should also start with an in-depth screening for and correc-
.. tion of suboptimal adherence, clinical inertia, inadequate drug combi-
..
.. nations, and excessive salt intake. Finally, adequate implementation of
.. new guidelines will contribute to diminish the prevalence of difficult
..
.. to control.
..
..
..
.. Funding
.. Spanish Institute of Health Carlos III (PI14/01841, CP15/00129, PI17/
..
.. 01093, PI17/01193, PI18/0139, PI16/02057, FI18/00261 and RETIC
.. REDINREN RD016/009); Fundación SENEFRO/Sociedad Espa~nola de
..
.. Nefrologı́a (SEN); Sociedad Espa~nola de Cardiologı́a (SEC); Comunidad
.. de Madrid en Biomedicina (B2017/BMD-3686 CIFRA2-CM); Luis
..
.. Hernando Project from Fundación Renal Í~nigo Álvarez de Toledo
.. (FRIAT); and Fondo Europeo de Desarrollo Regional (Fondos FEDER).
..
.. Conflict of interest: none declared.
..
..
..
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