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Diagnosis and management of resistant hypertension Miguel Camafort ,1,2 Reinhold Kreutz,3,4 Myeong-Chan Cho5
Diagnosis and management of resistant hypertension Miguel Camafort ,1,2 Reinhold Kreutz,3,4 Myeong-Chan Cho5
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Education in HeartDiagnosis and management of resistant hypertension
Miguel Camafort ,1,2 Reinhold Kreutz,3,4 Myeong-Chan Cho5
1
Hypertensión Unit. Internal ABSTRACT
Medicine Department, Hospital Learning objectives
Resistant hypertension is a condition where blood
Clinic de Barcelona, Barcelona,
Spain pressure levels remain elevated above target despite
⇒ To fully understand resistant hypertension's
2
CIBEROBN, Instituto de Salud changes in lifestyle and concurrent use of at least three
definition, prevalence, and prognosis.
Carlos III, Madrid, Spain antihypertensive agents, including a long-acting calcium
3
Charite Medical Faculty Berlin, ⇒ To discuss the procedures for conducting an
channel blocker (CCB), a blocker of the renin-angiotensin
Berlin, Germany effective resistant hypertension diagnostic.
4 system (ACE inhibitor or angiotensin receptor blocker)
Institut für Klinische ⇒ To examine the available alternatives for
Pharmakologie und Toxikologie, and a diuretic. To be diagnosed as resistant hypertension,
treating resistant hypertension, including
Berlin Institute of Health at maintaining adherence to therapy is required along
Charite, Berlin, Germany
pharmaceutical treatment, surgical intervention,
with confirmation of blood pressure levels above target
5
Cardiology, Chungbuk National and lifestyle advice.
by out-of-office blood pressure measurements and
University Hospital, Cheongju,
Korea exclusion of secondary causes of hypertension. The key
management points of this condition include lifestyle
Correspondence to changes such as reduced sodium and alcohol intake, of cognitive impairment and dementia.2 Antihyper-
Dr Miguel Camafort, Internal regular physical activity, weight loss and discontinuation tensive drug therapy has been shown to prevent its
Medicine, Hospital Clinic de of substances that can interfere with blood pressure development by lowering blood pressure (BP) in
Barcelona, Barcelona, Catalunya
08036, Spain;
control. It is also recommended that current treatment be patients with hypertension. Lifestyle modifications
camafort@clinic.cat rationalised, including single pill combination treatment are also crucial to lowering BP and preventing the
where antihypertensive drugs should be provided at the onset of newly diagnosed hypertension. Therefore,
maximum tolerated dose. It is further recommended that international guidelines have established BP goals to
current drugs be replaced with a more appropriate and determine when BP is under control in order to effi-
less difficult treatment regimen based on the patient’s ciently reduce CVD risk.3–5 Nevertheless, despite
age, ethnicity, comorbidities and risk of drug–drug initiation of lifestyle modifications and treatment,
interactions. The fourth line of treatment for patients with some patients have BP values that remain above the
resistant hypertension should include mineralocorticoid recommended goals. This condition could raise the
receptor antagonists such as spironolactone, as suspicion for resistant hypertension (RHT), related
demonstrated in the PATHWAY-2 trial and meta-analyses. by itself to a higher risk of developing CVD than the
Alternatives to spironolactone include amiloride, usual hypertension.6 It is essential to remember the
doxazosin, eplerenone, clonidine and beta-blockers, as precise definition of this condition to ensure rapid
well as any other antihypertensive drugs not already in identification, proper diagnosis and management.
use. New approaches under research are selective non- In this review, we will cover the definition, prev-
steroidal mineralocorticoid receptor antagonists such alence, aetiology, damage to target organs, CV
as finerenone, esaxerenone and ocedurenone, selective consequences, patient evaluation and therapy for
aldosterone synthase inhibitors such as baxdrostat, and RHT. However, it is crucial to bear in mind that a
dual endothelin antagonist aprocitentan. substantial portion of research on RHT was based
on observational studies, and that except for a few
recent randomised controlled trials (RCTs) there
INTRODUCTION are actually little reliable data. This paper will focus
Cardiovascular diseases (CVD) represent a global on recent developments while still upholding the
burden due to the high number of deaths and value of commonly recognised information.
disabilities they cause. One of the major risk
factors for CVD is hypertension. Hypertension DEFINITION OF RHT
is associated with a higher probability of sudden As one of the main criteria for RHT is having BP
death, cardiovascular (CV) and all-cause mortality, levels above target, we might observe slight differ-
ischaemic heart disease, heart failure (HF), atrial ences in the available definitions for RHT in the
fibrillation, stroke, chronic kidney disease (CKD), latest published guidelines. In the 2017 AHA/ACC,
cognitive dysfunction, dementia and peripheral 2018 European Society of Hypertension (ESH/
artery disease.1 European Society of Cardiology) and 2020 Inter-
© Author(s) (or their In the 2017 American College of Cardiology national Society of Hypertension hypertension
employer(s)) 2023. No (ACC)/American Heart Association (AHA) guide- guidelines, the goals to consider BP as controlled
commercial re-use. See rights
and permissions. Published
line for the prevention, detection, evaluation and are SBP levels below 140 mm Hg in European and
by BMJ. management of high blood pressure in adults, stage 1 international guidelines and below 130 mm Hg in
hypertension was defined as systolic blood pressure North American guidelines. The goals for DBP are
To cite: Camafort M, (SBP) values above 130 mm Hg and below 139 mm
Kreutz R, Cho M-C. Heart
below 90 mm Hg in European and international
Epub ahead of print: Hg, or diastolic blood pressure (DBP) values above guidelines and below 80 mm Hg in North American
[please include Day Month 80 mm Hg and below 89 mm Hg, as these values guidelines.3–5
Year]. doi:10.1136/ are related to a higher probability of mortality and The 2018 AHA scientific statement on detec-
heartjnl-2022-321730 disability due to CVD and also to an increased risk tion, evaluation and management of resistant
Camafort M, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321730 1
, Education in Heart
Figure 1 Diagnostic algorithm proposal for resistant hypertension. BP, blood pressure; CKD, chronic kidney disease.
hypertension defines RHT as the condition where be confirmed by out- of-
office BP measurements
the BP values of a patient with hypertension remain showing uncontrolled 24-hour BP (130 mm Hg SBP
elevated above target despite concurrent use of or 80 mm Hg DBP) values. Evidence of adherence
three antihypertensive agents of different classes, to therapy and exclusion of secondary causes of
commonly including a long-acting CCB, a renin- hypertension are required to define RHT, otherwise
angiotensin system (RAS) blocker (an ACE inhib- RHT is only apparent and called pseudo-RHT.8
itor or angiotensin receptor blocker) and a diuretic. The guidelines therefore recommend thoroughly
All agents should be administered at maximum or confirming uncontrolled office BP values through
maximally tolerated doses and at the appropriate measurement of BP values outside of the office as
dosing frequency. Patients with the white coat effect ambulatory BP measurement (ABPM) or home BP
should not be included in the definition of RHT, measurement (HBPM), confirming adherence to
and the diagnosis of RHT requires the exclusion therapy and properly ruling out secondary causes
of non-adherence to antihypertensive medications. of hypertension when RHT is suspected in order to
Finally, this position paper also includes patients have a case of true RHT. Pseudo-RHT is the condi-
with RHT whose BP shows values below target but tion where office BP shows lack of BP control,
are on four or more antihypertensive medications, a while ABPM or HBPM shows well-controlled BP.
condition that has been referred to in the literature Nevertheless, if obtaining ABPM or HBPM is not
as controlled RHT.7 feasible, epidemiological studies refer to this condi-
In the 2023 ESH guidelines, RHT is defined tion as apparent RHT. On the other hand, in some
as hypertension in patients who fail to lower patients, office BP values are below target, showing
office BP to ESH treatment goals (BP levels good control, but ABPM or HBPM values are
below <140/90 mm Hg) once appropriate life- clearly showing lack of BP control. This condition is
style measures and treatment with optimal or best called masked RHT.9 Finally, refractory HT is a type
tolerated doses of three or more drugs (specifying of RHT where BP remains uncontrolled despite
a thiazide/thiazide-like diuretic, an RAS blocker being on five or more antihypertensive drug classes,
and a CCB) have been initiated. The ESH guide- including a diuretic.
lines also specify that inadequate BP control should
Table 1 Causes of pseudo-resistant hypertension
Related situations Causes Viable solutions
Inaccurate office BP measurements. Inadequate BP measurement protocol. Obtain office BP readings according to recommended
protocol.
Perform out-of-office BP measurement (HBPM or
ABPM).
Non-adherence to prescribed antihypertensive drugs. Reluctance or inability to adhere to prescribed drug strategy due Single pill combination, direct observed therapy clinic.
to significant pill burden, complicated dosing, excessive cost, high
frequency of adverse reactions with multidrug antihypertensive
regimens.
Poor patient–clinician relationships.
Interfering substances: steroidal and non-steroidal anti-inflammatory drugs, and Increasing BP. It is mandatory to discontinue or minimise their effects
sympathomimetic drugs such as amphetamines, decongestants, stimulants, oral by adapting a treatment strategy for better BP control.
contraceptives, licorice and Ephedra.
ABPM, ambulatory BP measurement; BP, blood pressure; HBPM, home BP measurement.
2 Camafort M, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321730
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