REVIEW

Controversies in Hypertension V: Resistant and

Refractory Hypertension
Edward J. Filippone, MD,a Gerald V. Naccarelli, MD,b Andrew J. Foy, MDb
a
Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pa;
b
Department of Medicine, Penn State University Heart and Vascular Institute, Penn State M.S. Hershey Medical Center and College of
Medicine, Hershey, Pa.

ABSTRACT

Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive
medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15%
of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite
use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated
with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-
refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regi-
men, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by vol-
ume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the
preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred
if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated.
The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (a-b blockade, cen-
trally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit
for resistance, but its role in refractory hypertension remains to be defined.
Ó 2023 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2024) 137:12−22

KEYWORDS: Ambulatory blood pressure monitoring; Finerenone; Home blood pressure monitoring; Hypertension;
Mineralocorticoid receptor antagonists; Refractory hypertension; Resistant hypertension; Renal denervation;
Spironolactone

INTRODUCTION methodology, inappropriate dosages or combinations of

Resistant hypertension is defined as either the inability to
achieve blood pressure control despite administration of ≥ 3
antihypertensive medications at maximal, or maximally tol-
erated, dosages, including a diuretic, or controlled pressure
requiring ≥ 4 medications.1 Usual 3-drug regimens include
a renin-angiotensin system inhibitor, calcium channel
blocker, and a thiazide or thiazide-like diuretic. Many cases,
probably most, are not truly resistant but are pseudo-resis-
tant, caused by inappropriate blood pressure determination
Funding: None.
Conflict of Interest: GVN reports consulting for Sanofi, Glaxo, Smith
Kline, Acesion, and Milestone.
All other authors report no conflicts of interest.
Authorship: All authors had access to the data and a role in writing
this manuscript.
Requests for reprints should be addressed to Edward J. Filippone MD,
2228 South Broad St., Philadelphia, PA, 19145.
E-mail address: edward.filippone@jefferson.edu
agents, a white-coat effect, non-adherence, or a combination
of these factors. Until all concerns are addressed, the appro-
priate designation is apparent resistant hypertension.
Patients with controlled blood pressure requiring ≥ 4 med-
ications are resistant but are termed “controlled resistant.”
Within the phenotype of uncontrolled resistant hypertension
is the more severe phenotype termed “refractory hyper-
tension,” defined as the inability to adequately control pres-
sure despite ≥ 5 medications, including a diuretic.2 The most
rigorous definition specifies long-acting thiazide (chlorthali-
done) and mineralocorticoid receptor antagonist (spironolac-
tone) are included.3 Possible phenotypes include controlled
resistant hypertension (on ≥ 4 medications), uncontrolled
resistant hypertension (on 3-4 medications), and refractory
hypertension (uncontrolled on ≥ 5 medications).
The purpose of this review is to highlight the approach to
the patient with apparent resistant or refractory hypertension

0002-9343/© 2023 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.amjmed.2023.09.015

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Filippone et al Controversies in Hypertension V: Resistant and Refractory Hypertension 13

and the clinical significance. Pathophysiology will be dis- hypertension when both are below threshold, uncontrolled
cussed, and current treatment trials will be reviewed. when both are above, white-coat effect when office is above
threshold but out-of-office below, and masked when the
reverse occurs. Considering the number of prescribed anti-
PSEUDO-RESISTANT HYPERTENSION hypertensive medications increases the number of pheno-
Most patients with apparent resistant hypertension have types (Table 2).
pseudo-resistance. The first issue is assuring proper meth- A white-coat effect may be found in 28%-53% of patients
odology of pressure determination (Table 1).4 Of 130 with apparent treatment resistant hypertension10−12 and in
patients referred to a hypertension specialty clinic with 10%- 27% with apparent refractory hypertension.3,13,14 Out-
apparent resistant hypertension, of-office pressure is best assessed by
33% of uncontrolled patients based ambulatory monitoring, but home
CLINICAL SIGNIFICANCE
on a single triage pressure deter- blood pressure monitoring may be
mined initially in a common area
Apparent resistant hypertension is used. Available data indicate both
were found to have controlled pres- 12,15,16
uncontrolled office pressure despite 3 white-coat resistant and white-
sures at the same visit when 13,14
medications, including a diuretic, or coat refractory cases have
obtained by trained physicians controlled pressure on 4 medications. reduced cardiovascular risk. No
using guideline-based
guidelines recommend intensification
Apparent refractory hypertension is
methodology.5
The antihypertensive regimen
uncontrolled office pressure despite 5 of therapy for white-coat resistant or
refractory hypertension.
must be appropriate, usually medications, including a diuretic and
Assessment of medication adher-
defined as containing a diuretic and preferably spironolactone. ence is critical.17−20 Although there
all other medications at ≥ 50%
Pseudo-resistance, caused by improper is no gold standard, multiple tools
maximal dose. Although low-dose technique, inadequate antihyperten- are available. Indirect methods
combination therapy may improve sive regimen, white-coat effect, non- include patient self-report (via ques-
6
both blood pressure control and adherence, or a combination of these tionnaire, interview, or diary), direct
adherence,6,7 a patient should not factors, must be excluded. pill counts, electronic pill boxes
be considered resistant unless each
Treatment of resistance should include activated upon opening, and pre-
individual dose is optimal,8,9 spironolactone if kidney function scription registries.
20,21
Direct meth-
including those within combina- allows. ods include directly observed
tions. In a study of 468,877 hyper-
therapy followed by a 24-hour
Treatment of refractory hypertension
tensive subjects, 44,684 had ambulatory monitoring session,
apparent treatment resistant hyper-
needs defining.
therapeutic drug monitoring of
tension of which 22,495 (»50%) blood or urine by high-performance
were suboptimally treated due liquid chromatography followed by
either to ≥1 medication at < 50% maximal dose (18,792) or tandem mass spectrometry (termed “chemical adherence
lack of a diuretic (3703).8 testing”), and ingestible event monitors. There are pros and
Out-of-office pressure must be assessed to exclude the cons of each method (Table 3). Non-adherence is dynamic
white-coat effect. There are 4 phenotypes of treated hyper- and variable over time.20
tensive patients comparing office and out-of-office blood Physician perception of adherence is notoriously inaccu-
pressures with their respective thresholds: controlled rate, perhaps no better than a coin toss.22 However, lack of
an expected biologic response suggests non-adherence,
Table 1 Proper Blood Pressure Determination Methodology such as an elevated heart rate (>75) despite b blockade23 or
failure to decrease blood pressure upon adding medications.
1. 5 minutes of quiet rest.
Counting remaining tablets is time-consuming and raises
2. Feet on floor, legs uncrossed.
3. Back supported.
hygienic issues. Patient self-reporting is easy and cheap but
4. Arm bare and supported at the level of the heart. is susceptible to unintentional (forgetfulness, complex regi-
5. Correct cuff size (bladder covers 80% of arm mens) or intentional (side effects, cost, depression, lack of
circumference). understanding) inaccuracy. Multiple questionnaires have
6. No mobile phone use or talking. been developed,21 although validating studies have shown
7. Pressure obtained in both arms with notation of the arm poor to modest validation.24,25
with higher reading for future use. Pharmacy prescription refill rates can be assessed to
8. Obtain ≥ 2 measurements separated by 1−2 minutes on ≥ calculate the number of days potentially covered; adher-
2 occasions to estimate blood pressure load. ence is defined as > 80%.26 Electronic medication
9. Avoid caffeine, exercise, and smoking for at least 30 event-monitoring systems can record the date and time a
minutes.
pillbox was opened.27 However, neither prescription
10. Ensure the bladder is emptied.
refills nor pillbox opening ensures the medication was
ingested.

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14 The American Journal of Medicine, Vol 137, No 1, January 2024

Table 2 Phenotypes of Hypertensive Patients on Antihyper-
tensive Medications
Controlled hypertension*: office blood pressure below 130/
80y and out-of-office below 130/80 daytime or 125/75 24-
hour
- On 1−3 medications: controlled hypertension
- On ≥ 4medications: controlled resistant hypertension
Uncontrolled hypertension: office SBP > 130 or DBP > 80 and
out-of-office daytime SBP > 130 or DBP > 80 or 24-hour SBP >
125 or 24-hour DBP > 75
- On 1−2 medications: uncontrolled hypertension
- On 3−4 medications: uncontrolled resistant
hypertension
- On ≥ 5 medicationsz: refractory hypertension (uncon-
trolled by definition).
White-coat effect: office SBP > 130 or DBP > 80 and out-of-
office below 130/80 daytime or 125/75 24-hour
- On 1−2 medications: white-coat effect
- On 3−4 medications: white-coat resistant hypertension
- 0n ≥ 5 medications: white-coat refractory hypertension
Masked effect: office blood pressure below 130/80 and out-of-
office daytime SBP > 130 or DBP > 80 or 24-hour SBP > 130 or
24-hour DBP > 80
- On 1−2 medications: masked hypertension
- On 3−4 medications: masked resistant hypertension
- On ≥ 5 medications: masked refractory hypertension
DBP = diastolic blood pressure; SBP = systolic blood pressure.
*Based on 2018 American College of Cardiology/American Heart
Association Guidelines.4
yAll pressures in mmHg.
zIncluding a long-acting thiazide-like diuretic (chlorthalidone or
indapamide) and steroidal mineralocorticoid antagonist (spironolac-
tone or eplerenone if kidney function allows).
Directly observed therapy is followed by a short period of
observation and then 24-hour ambulatory monitoring.28−31
Of 37 patients referred for specialist care, 15 had pressures <
140/90 (all pressures in mmHg) by 2 hours after direct
directly observed therapy with further lowering of 8/5 during
the subsequent 24-hour monitoring.28 Of 18 patients referred
for renal denervation, 5 had normal daytime ambulatory sys-
tolic pressure following directly observed therapy despite ele-
vated clinic pressures and elevated prior ambulatory
pressures in 3.29 Of 65 patients referred for renal denervation,
19 had normal ambulatory pressure after directly observed
therapy, including 13 with previously elevated ambulatory
pressures.30 Non-adherence was defined as ambulatory pres-
sure following directly observed therapy ≥ 5 mmHg lower
compared with prior ambulatory monitoring and was found
to be up to 50%.31
An ingestible event monitor may be incorporated
whereby a sensor gets activated by acid in the stomach
transmitting a unique digital signal to a wearable sensing
patch that has a mobile-based interface to record drug
ingestion in real time.32 This methodology is not generally
available.
At least 15 studies involving 2890 patients utilized chemi-
cal adherence testing to assess adherence to antihypertensive
therapy 3,33−46; over 800 had apparent resistant hypertension,
including 40 with true refractory hypertension3 (Table 4).
Most of the apparent resistant cases had excluded the white-
coat effect. Non-adherence of apparent resistant patients
ranged from 37.9% to 86.1% averaging about 50%, probably
a significant underestimation because not all drugs could be
assayed, and such testing lends itself to “white-coat
adherence” (enhanced temporary compliance given

Table 3 Indirect and Direct Methods of Adherence Assessment

Indirect Direct
Pros Cons Pros Cons
Physician perception Easy, inexpensive, readily Notoriously inaccurate Directly observed therapy Determines response to Hypotension if previously
available followed by ABPM actual ingestion non-adherent
Patient self-report or Easy, inexpensive, readily Unintentional or inten- Chemical adherence Blood or urine Cannot verify correct dos-
diary available tional inaccuracies* testing Proves drug ingested age and/or frequency.
May improve adherence Susceptible to “white-
with repeated testing coat adherence” and
the “toothbrush
effect”y
Not widely available
Requires knowledge of
pharmacokinetics
Susceptible to alterations
in drug metabolismz
Questionnaires Easy, inexpensive, readily Inaccurate when tested Ingestible event Proves ingestion Not widely available
available monitors
Pill counting Quantitative Time-consuming
Not hygienic
ABPM = 24-hour ambulatory blood pressure monitoring.
*Unintentional: overwhelmed from polypharmacy and complex regimens, forgetful. Intentional: cost prohibitive, side-effects, depression, lack of
understanding of risks and benefits.
yWhite-coat adherence and toothbrush effect refer to changes in behavior (adherence) resulting from knowledge that a physician encounter is pend-
ing, and adherence will be assessed.
zAlterations in drug metabolism may occur with intercurrent illnesses (eg, gastroenteritis, diarrhea, hepatic or renal disease) or concurrent ingestion of
drugs altering pharmacokinetics (eg, inducers or inhibitors of relevant cytochrome p450 metabolizing enzymes)

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Filippone et al Controversies in Hypertension V: Resistant and Refractory Hypertension 15

Table 4 Adherence Determination by Liquid Chromatography-Tandem Mass Spectrometry in Blood or Urine

Author/Year Number Population WCE Source Adherence % Non-adherent Comments
Excluded Complete/Partial/
None
Ceral/201133 84 Difficult-to-control Yes Blood 29/26/29 65.5% First study to use LC-MS/MS in
this population.
Strauch/201334 339 163 outpatients with Yes Blood 53/24/23 47% of outpatients Hospitalized to rule out secondary
aRH (81/9/10) (9% hospitalized) causes.
(176 hospitalized to 69.4% of antihypertensive drugs
rule out secondary in outpatients analyzed.
causes)
Jung/201335 76 aRH Yes Urine 36/28/12 47.4% 0f 388 prescribed drugs, 368 ana-
lyzed. Excluded 17 controlled
on 4 drugs.
Brinker/201436 56 aRH No Blood 26/12/18 54% All 30 non-adherents initially
denied non-adherence. BP
reduced by 46/26 mmHg on fol-
low-up after counselling
Tomaszewski/201437 208 Group A: 125 new Partial Urine A: 102/12/11 A: 18.4% Many in group A would not clas-
referrals B: 41/19/6 B: 37.9% sify as aRH.
Group B: 66 aRH C: 13/0/4 C: 23.5%
Group C: 17 referred
for RD
Florczak/201538 36 aRH Yes Blood 5/26/5 86.1% Excluded patients with reduced
kidney function or diabetes.
Required use of ≥ 4 medica-
tions.
Ewen/201539 100 aRH referred for RD Yes Blood/urine 52/46/2 48% At 6-month follow-up after RD,
non-adherence increased to
57%
Patel/201640 24 Referred for RD Yes Urine 16/4/4 33% Not all aRH. Only 1 eventually
denervated
41
Schmieder/2016 79 aTRH referred for RD Yes Urine 44/22/13 44% All were denervated.
0At 6-month follow-up after RD:
Non-adherence decreased to 34%
Hamdidouche/ 174 Referred to hyperten- Partial Urine 159/12/3 9% Not restricted to aRHT (average of
201742 sion clinic 2.6 drugs/patient), only 46/
174 uncontrolled at home.
Pucci/201743 131 aRH or referred for No Urine 67/43/21 49% 45% complete adherence in the
RD 122 on ≥ 3 medications
Gupta/201744 1,348 Hypertension, sus- Urine: UK cohort 395/183/98 UK 41.6% UK Not restricted to aRHT.
676 UK pected non-adher- Blood: Czech cohort 460/131/81 Czech 31.5 Czech WCE not excluded
672 Czech ence in UK;
difficult to control
BP in Czech
Siddiqui/20203 40 aRfH Yes Urine 16/18/6 40% Uncontrolled on 5 medications,
including chlorthalidone and a
MRA. Of 18 with partial adher-
ence, 5 had 5 medications
detected including chlorthali-
done and a MRA (hence true
RfH)
Only 5 (of 45) had WCE
Georges/202145 53 KT recipients No Urine 42/8/3 21% Not restricted to aRHT. Only 2.1
drugs/patient
Peeters/202346 142 Uncontrolled on ≥ 2 No Blood 45/18/3 31.8% By multivariable analysis only
66 drugs aRHT having a KT significantly asso-
ciated with adherence
aRfHT = apparent refractory hypertension; aRHT = apparent resistant hypertension; BP = blood pressure; KT = kidney transplant recipient; LC-MS/
MS = liquid chromatography − tandem mass spectrometry; MRA = Mineralocorticoid Receptor Antagonists; RD = renal denervation; UK = United Kingdom;
WCE = white coat effect.

knowledge of being tested). Furthermore, a positive assay
only proves some drug taken, not necessarily fully prescribed
dosages or frequencies.
Using such data to inform and educate non-adherent
patients may improve adherence and pressure control.
Brinker et al notified 16 non-adherent patients with the
results of blood monitoring followed by counselling to
improve adherence; blood pressure was subsequently
reduced by 46/27 compared with pre-screening.36 Gupta et
al studied 73 non-adherent patients that were informed and
counseled about the results of which 30 had repeat analyses.
Eventually, 80% improved adherence, including 53%
completely. Pressure significantly improved without addi-
tional medication and the reduction was directly associated
with the urinary adherence ratio (number detected divided
by number prescribed).47

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16
FREQUENCY AND SIGNIFICANCE OF RESISTANT
HYPERTENSION
Most assessments of frequency consider apparent resistance
because out-of-office pressures or adherence data are not
available.48 The 2018 American Heart Association Scien-
tific Statement on resistant hypertension cites prevalence of
12%-15% in population-based and 15%-18% in clinic-
based studies of treated hypertensives.1 A meta-analysis of
91 studies (3,207,911 hypertensive participants) found
apparent resistance in 14.7%, and in the studies capable of
making the distinction, 10.3% pseudo-resistance and 10.3%
true resistance.49 Apparent refractory hypertension has a
prevalence of ≤ 10% of resistant patients.13,14
Many studies utilized the earlier threshold for control of
140/90, whereas others used the current cutoff of 130/80.
Carey et al analyzed NHANES data and found the preva-
lence of apparent resistance increased from 17.7% to 19.7%
utilizing the stricter criteria,50 and Chun et al found the
prevalence increased from 10.2% to 13.7% studying 2018
Korean patients.51 A recent analysis of 1,343,489 hyperten-
sive participants of 3 large healthcare systems (2,420,468
total patients) found 8.5% had apparent resistance (4.7% of
the entire population) using 130/80 mmHg.52 Utilizing a
140/90 cutoff, 8.3% of hypertensives (3.2% of all patients)
were apparently resistant.
Resistance is associated with other comorbidities,
including obesity,53 sleep apnea,54 diabetes,55 chronic kid-
ney disease,56 and kidney transplants (56%).49 Of 3147
hypertensive patients with chronic kidney disease in the
Chronic Renal Insufficiency Cohort, 36.3% had apparent
resistance, including 4.3% with apparent refractory
hypertension.57
Intermediate cardiovascular endpoints are increased with
resistance, including left ventricular hypertrophy,58 carotid
atherosclerosis,58 and albuminuria.59 Determination of
resistance should prompt appropriate evaluation. Further-
more, the risk for future cardiovascular and renal events is
increased.60 The extreme phenotype of refractory hyperten-
sion has higher comorbidity than resistant but non-refrac-
tory hypertension61 and further enhanced risk for future
cardiovascular events.14
PATHOPHYSIOLOGY
Resistant hypertension is predominantly mediated by sodium
retention,52 volume overload,62 and aldosterone.63 Studying
patients with apparent resistant hypertension, Calhoun et al
found 20% of 88 had primary hyperaldosteronism.64 As did
Brown et al in 22% of 408.63 Gaddam et al compared 279
patients with apparent resistant hypertension with 53 non-
resistant controls with obstructive sleep apnea and found the
resistant cases had a higher aldosterone/renin ratio, higher
plasma aldosterone, higher 24-hour urinary aldosterone,
lower plasma renin, and higher natriuretic peptides than con-
trols.65 Significant pressure lowering in resistant hyperten-
sion with baxdrostat, an aldosterone-synthase inhibitor,
attests to aldosterone’s role.66 In contrast, refractory
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The American Journal of Medicine, Vol 137, No 1, January 2024
hypertension appears to be mediated by enhanced sympa-
thetic tone,67 not excessive volume.68 Compared with
patients with controlled resistant hypertension, refractory
cases were shown to have higher urinary norepinephrine,
higher heart rate, reduced heart rate variability, higher sys-
temic vascular resistance,67 but not increased left atrial vol-
ume, left ventricular volume, or natriuretic peptide levels.68
THERAPY
Lifestyle modification, salt restriction, and avoidance of
antagonizing medications are implicit. Given the predomi-
nance of volume overload and aldosterone excess in resis-
tant hypertension, multiple studies assessed the blood
pressure lowering effect of steroidal mineralocorticoid
receptor antagonists, including the unselective spironolac-
tone (affecting mineralocorticoid, androgen, and progester-
one receptors) and relatively more selective, but less
potent, eplerenone. A meta-analysis of 15 studies, including
3 placebo-controlled randomized controlled trials, 1 non-
randomized comparative study, and 11 single-arm studies,
with 1204 total patients found steroidal aldosterone antago-
nists reduced systolic blood pressure by 24.26 mmHg
(P = .002) in comparative studies and by 22.74 (P <
.00001) in single-arm studies; diastolic blood pressure was
also significantly reduced.69 Two other meta-analyses pro-
duced similar results.70,71
Studies have compared spironolactone with other active
agents as fourth-line therapy for resistant hypertension.
Wiliams et al compared spironolactone with sympathetic
inhibition with the a1-blocker doxazosin and to the b1-
blocker bisoprolol for 12 weeks each in 335 patients
(PATHWAY-2) and found spironolactone reduced home
systolic blood pressure by 8.7 compared with placebo and
by »4.5 compared with the other 2 drugs either averaged
together or considered separately (all P < .0001).72 Only 6
of 285 patients receiving spironolactone developed serum
potassium > 6.0 mmol/L. A meta-analysis of 2 randomized
trials (including PATHWAY-2) and 3 non-randomized
studies confirmed the superiority of spironolactone over
other comparators as fourth-line agents; only 12 of 424
patients developed hyperkalemia.73
Multiple trials assessed the effects of steroidal mineralo-
corticoid receptor antagonists on hard endpoints, although
not specifically in resistant hypertension. Spironolactone
reduced morbidity and mortality in patients with heart fail-
ure with reduced ejection fraction,74 although not with pre-
served ejection fraction.75 Eplerenone was similarly
beneficial after myocardial infarction complicated by heart
failure,76 but not without heart failure.77,78 A meta-analysis
of 31 trials of mineralocorticoid receptor antagonism (3
with finerenone) revealed a significant decrease in albumin-
uria (proteinuria) with a decrease in estimated glomerular
filtration rate (eGFR) and a significantly increased risk of
hyperkalemia,79 mirroring a prior 2014 Cochrane review.80
The use of steroidal aldosterone receptor antagonists for
resistant hypertension may be precluded from patients with
Filippone et al Controversies in Hypertension V: Resistant and Refractory Hypertension 17

reduced eGFR (eg, < 45 mml/min/1.73m2) for fear of
hyperkalemia or eGFR reduction. If concurrently receiving
renin-angiotensin system inhibitors, the risk for hyperkale-
mia may double.80 When given to normotensive patients
with heart failure with preserved ejection fraction in one
trial, patients with eGFR 30 - < 45 had triple the rate of
hyperkalemia than with eGFR ≥ 60 and nearly twice the
rate of doubling of serum creatinine.81
A 2020 Cochrane review of aldosterone antagonist use
with chronic kidney disease concluded they increase the
probability of both hyperkalemia (risk ratio 2.17) and acute
kidney injury (risk ratio 2.04) compared with placebo or
standard care with moderate certainty.82 Some authors rec-
ommend use of spironolactone for resistant hypertension
with eGFR 30 to 45 but starting with a low dose (12.5 mg)
with careful electrolyte follow up.83
To test the safety of spironolactone, 295 patients with
apparent resistant hypertension and eGFR 25 - ≤ 45 were
treated with spironolactone 25-50 mg/day and randomized to
patiromer or placebo (AMBER Trial).84 At 12 weeks, 86%
of patients receiving patiromer remained on spironolactone
vs 66% receiving placebo (P < .0001). Similar results
obtained in subgroups with diabetes85 and heart failure.86
In addition to the distal nephron, the aldosterone receptor
is expressed in both kidney non-epithelial tissue and multiple
other sites, including myeloid cells, heart, vasculature, brain,
and eye.87 Activation of these non-epithelial sites produces
oxidative stress and promotes inflammation and fibrosis. In
addition to steroidal receptor antagonists, multiple nonsteroi-
dal agents are being studied for blood pressure lowering and
end-organ protection (see Table 5). These differ from their
steroidal counterparts in tissue distribution, selectivity,
cofactor recruitment capability, and degree of antagonism,
and they have less propensity for hyperkalemia.88,89
Esaxerenone was shown to be effective compared with
placebo in a study of 426 Japanese patients with stage 2
primary hypertension.90 Bakris et al compared ocedurenone
(0.25 and 0.5 mgs) with placebo in 162 patients with uncon-
trolled, stage 2 hypertension (89% apparently resistant) and
stage 3b/4 chronic kidney disease and found placebo-con-
trolled reductions of systolic pressure of 7-10 at 12 weeks;
hyperkalemia was non-significantly but numerically higher
with ocedurenone (11.8%-16.7% vs 8.8%) although no
cases required intervention or discontinuation.91 These
effects were consistent among various subgroups based on
ethnicity, eGFR, degree of albuminuria.92 Agarwal et al
indirectly compared the systolic blood pressure lowering
effect of finerenone to spironolactone in a post-hoc analysis
of apparently resistant hypertensive patients with kidney
disease from 2 trials (ABBER and PATHWAY-2) and
found both a greater blood pressure lowering effect (»11 vs
»7) and more hyperkalemia (35-64% vs 11.6%) with
spironolactone.93
Nonsteroidal mineralocorticoid receptor antagonists
have been studied in several randomized controlled trials
assessing intermediate94−98 or hard endpoints (see Table
6).99−102 Finerenone was compared with placebo in diabetic
patients with kidney disease in 2 trials showing significant
reductions in kidney (kidney failure, reduction of eGFR, or
death from kidney failure) and cardiovascular (cardiovascu-
lar death, non-fatal myocardial infarction, non-fatal stroke,
hospitalization for heart failure) outcomes in over 13,000
patients.99−101 Pressure was slightly reduced, although
hyperkalemia was significantly increased.
Subsequent therapy should target the sympathetic nervous
system with a-b blockade followed by centrally acting sym-
patholytic agents, vasodilators, or both, if pressure remains
uncontrolled. Renal denervation appears ineffective,103
because resistance is predominantly volume mediated.
Because refractory hypertension may be mediated by
enhanced sympathetic tone, therapy should be directed
accordingly. A small proof-of-concept study showed a

Table 5 Comparison of Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists

Steroidal MRAs Nonsteroidal MRAs
Agents Spironolactone Esaxerenone (available in Japan for hyperten-
Eplerenone sion)
Finerenone (available in the United States for
diabetic kidney disease)
Ocedurenone (efficacy in resistant hypertension)
Apararenone
Balcinrenone
Tissue distribution Kidney >> heart Kidney = heart (finerenone, in a rodent model) 107
Coregulator recruitment 87,108 Inhibition (in presence of aldosterone) Inhibition in presence or absence of aldosterone
Partial agonists in aldosterone absence (finerenone)
May explain reduced tendency for hyperkalemia
Crosses blood/brain barrier Yes (may explain greater hypertensive effect by No
blocking CNS MRAs 89)
Half-life Spironolactone and active metabolites > 24 hours Finerenone: 2−3 hours
(detectable for weeks 84)
Eplerenone 4−6 hours
CNS = central nervous system; MRA = mineralocorticoid receptor antagonists.

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 18
Table 6 Randomized Controlled Trials of Non-steroidal Mineralocorticoid Receptor Antagonists with Intermediate or Hard Endpoints
Trial and Year Medication Comparator Number Population Primary Endpoint Result/Significance BP Effect Comment

Trials with intermediate endpoints

ARTS-II 94 Finerenone Placebo or spironolactone 389 Change in serum K Less rise in K vs spironolac- SBP similar to placebo, less Reduced BNP and NT-proBNP similar to spironolactone
2013 Variable dosage: HFrEF and moderate CKD tone (<0.0001-0.0107) than spironolactone
2.5, 5, 10 mg/day or 5 mg/ but greater than placebo
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bid
ARTS-DN 95 Finerenone, Placebo 823 Change in UACR ratio from Significant reduction in SBB reduced more than pla- Overall incidence of K ≥ 5.6 1.8% in 7.5-20 mg/day
2015 variable dosage: Type 2 DM, K ≤ 4.8, albu- baseline to day 90 7.5, 10, 15, and 20 mg cebo at 90 days in 15 groups
1.25, 2.5, 5, 7.5, 10, 15, minuria, eGFR ≥ 30, on groups vs placebo and 20 mg groups
and 20 mg/day RAS blockade P < .004-.001
96
ARTS-DN Japan Finerenone Placebo 96 Change in UACR ratio from Reduced significantly only SBP decreased in 7.5, 10, Small increases in serum K
2017 Variable dosage: Type 2 DM, UACR ≥ baseline to day 90 for 20 mg/day and 20 mg/day groups
1.25, 2.5, 5, 7.5, 10, 15, 20 30 mg/g on RAS
mg/day blockade
Ito et al. 97 Esaxerenone Placebo 365 Change in UACR from base- Significant reduction for Significant reductions in Adverse events slightly more with active drug, most
2019 Variable dosage: Type 2 DM, UACR ≥ 45 - < line to week 12 1.25, 2.5, and 5 mg/day sitting SBP/DBP with 2.5 often hyperkalemia (dose related)
0.625, 1.25, 2.5, or 5 mg/ 300 mg/g, eGFR ≥ 30, on vs placebo and 5 mg/ doses
day RAS blockade All P < .001
ESAX-DN 98
Esaxerenone Placebo 455 UACR remission at 52 weeks 22% vs 9 % (placebo) Significant reductions in Reduced progression to UACR ≥ 300
2020 1.25 titrated to 2.5 mg/day Type 2 DM, UACR ≥ 45 - < P < .001 sitting SBP/DBP Greater hyperkalemia with active drug
300 mg/g, eGFR ≥ 30, on
RAS blockade
Trials with hard endpoints
FIDELIO-DKD 99 Finerenone Placebo 2,833 Kidney failure, eGFR Hazard ratio 0.82 SBP decrease 2.1 mmHg at Hazard Ratio of secondary CV composite (CV death, MI,
2020 Type 2 DM with either UACR decrease of ≥ 40%, or P = .001 12 months vs increase stroke, HHF) 0.86
30 - < 300 and eGFR 25 - death from renal causes (median follow-up 2.6 0.9 placebo P = .03
< 60 or UACR 300 − years) UACR decreased 31% greater than placebo at 4 months

The American Journal of Medicine, Vol 137, No 1, January 2024

5000 with eGFR 25 - <75 that maintained.
Hyperkalemia AEs 18.3% finerenone vs 9% placebo.
2.3% finerenone vs 0.9% discontinuation for
hyperkalemia
FIGARO-DKD 100 Finerenone Placebo 7437 CV death, MI, stroke, HHF Hazard ratio 0.87 SBP decreased by 2.6 Hazard ratio of kidney outcome (kidney failure, eGFR
2021 Type 2 DM with either UACR P = .03 mmHg at month 24 decrease of ≥ 40%, or death from renal causes) 0.87
30 - < 300 and eGFR 25 - (median follow-up 3.4 (P = NS).
< 90 or UACR 300−5000 years) UACR decreased 32% greater than placebo at 4 months.
with eGFR > 60 Hyperkalemia 10.8% finerenone vs 5.3% placebo.
1.2% finerenone vs 0.4% discontinuation for hyperka-
lemia.
FIDELITY 101 Finerenone Placebo 13,026 1. CV death, MI, stroke, 1. Hazard ratio 0.86 SBP decrease of 3.2 mmHg UACR decreased 32% greater than placebo at 4 months
2022 Combined patients from HHF. P = 0.0018 vs increase 0.5 with pla- that maintained.
FIDELIO-DKD and FIG- 2. Kidney failure, eGFR 2. Hazard ratio 0.77 cebo at 4 months Hyperkalemia 14.0% finerenone vs 6.9% placebo.
ARO-DKD decrease of ≥ 57%, or P = .0002 1.7% finerenone vs 0.6% discontinuation for hyperka-
death from renal causes lemia.
Sarafidis et al. 102 Finerenone Placebo 890 1. CV death, MI, stroke, 1. Hazard ratio 0.78 SBP decrease of 2.0 mmHg UACR decreased 31% greater than placebo at 4 months
2023 FIDELITY patients with HHF. P = NS vs increase 1.7 with pla- that maintained through 24 months.
Stage-4 CKD 2. Kidney failure, eGFR 2. Not calculated as pro- cebo at 4 months Finerenone attenuated decline of eGFR from month 4
decrease of ≥ 57%, or portional hazards until the end (p = 0.04) but not from baseline until
death from renal causes assumption not met the end (P = .22).

AE = adverse event; BID = 2 times a day; BNP = brain natriuretic peptide; CKD = chronic kidney disease; CV = cardiovascular; DBP = diastolic blood pressure; DM = diabetes mellitus; eGFR = estimated glomerular
filtration rate; HHF = hospitalization for heart failure; MI = myocardial infarction; NT-proBNP = n-terminal pro brian natriuretic peptide; RAS = renin-angiotensin system; SBP = systolic blood pressure;
UACR = urine albumin-to-creatinine ratio.
Filippone et al Controversies in Hypertension V: Resistant and Refractory Hypertension
benefit to reserpine,104 and a post-hoc analysis of a trial of
CPAP in obstructive sleep apnea showed a greater blood
pressure lowering effect in refractory than resistant
cases,105 as did renal denervation.106
DISCUSSION
Apparent resistant hypertension affects about 10%-15%
of treated hypertensives, and refractory hypertension
about 10% of resistant cases. It is imperative to rule out
pseudo-resistance, which underlies 50% or more of
apparent resistance. Guideline-based blood pressure
determination should be utilized. A standard 3-drug regi-
men includes a renin-angiotensin inhibitor, calcium
channel blocker, and thiazide or thiazide-like diuretic,
all of which should be at maximal, or maximally toler-
ated, dosage (≥ 50% of maximal). Out-of-office pressure
must be determined, preferably with ambulatory moni-
toring (or home monitoring if ambulatory is not avail-
able). Adherence should be assessed, preferably by
chemical adherence testing.
White-coat resistance should not prompt intensification
of therapy, although it should be validated on repeat testing.
If non-adherence is confirmed, the patient should be
approached in a non-judgmental manner to determine the
cause, whether intentional, non-intentional, or both, and
appropriate measures implemented to correct the cause(s).
True resistant hypertension necessitates evaluation for
secondary causes of hypertension (Table 7) with appropri-
ate treatment if found. True primary resistant hypertension
Table 7 Secondary Causes of Resistant Hypertension and
Appropriate Testing
Chronic kidney disease (cause and result of resistant hyperten-
sion)
eGFR
Urinalysis/urine albumin
Obstructive sleep apnea
Polysomnography
Primary hyperaldosteronism
24-hour urine aldosterone (≥ 12 ng) 63
Suppressed plasma renin activity (< 1 ng/ml/hr)
Suggested by aldosterone/renin ratio > 20
Renovascular hypertension
Doppler ultrasound, CT angiogram, or MRA
Pheochromocytoma
Plasma metanephrines (note: levels elevated 2-3 times in
chronic kidney disease stages 4-5 109)
Coarctation of the aorta
Physical examination
Other (rare) causes to consider based on clinical evaluation
Cushing syndrome
Thyroid dysfunction
Congenital adrenal hyperplasia
Acromegaly
Hyperparathyroidism
CT = computed tomography; eGFR = estimated glomerular filtration
rate; MRA = mineralocorticoid receptor antagonists.
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19
confers higher cardiovascular risk and necessitates intensifi-
cation. If the eGFR is > 45, the next drug should be a min-
eralocorticoid receptor antagonist. Current data support
steroidal antagonists, especially if congestive heart failure
with reduced ejection fraction; however, if elevated urinary
albumin, end-point data support finerenone despite less
pressure lowering effects. If the eGFR is between 30 and
45, steroidal agents may be considered, with concurrent K-
binder, at half-standard dose, or both, but only with close
follow-up of serum potassium; finerenone should be used
with elevated urine albumin when the eGFR is > 25. Subse-
quent therapy should target the sympathetic nervous system
(combined a-b blockade) followed by centrally acting
agents or vasodilators. Therapy of refractory hypertension
requires maximal sympathetic suppression, although ran-
domized trials are clearly needed.
References
1.. Carey RM, Calhoun DA, Bakris GL, American Heart Association
Professional/Public Education and Publications Committee of the
Council on Hypertension; Council on Cardiovascular and Stroke
Nursing; Council on Clinical Cardiology; Council on Genomic and
Precision Medicine; Council on Peripheral Vascular Disease; Coun-
cil on Quality of Care and Outcomes Research; and Stroke Council.
Resistant hypertension: detection, evaluation, and management: a
scientific statement from the American Heart Association. Hyperten-
sion 2018;72(5):e53–90.
2. Matanes F, Khan MB, Siddiqui M, Dudenbostel T, Calhoun D,
Oparil S. An update on refractory hypertension. Curr Hypertens Rep
2022;24(7):225–34.
3. Siddiqui M, Judd EK, Dudenbostel T, et al. Antihypertensive medi-
cation adherence and confirmation of true refractory hypertension.
Hypertension 2020;75(2):510–5.
4. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the
prevention, detection, evaluation, and management of high blood
pressure in adults: Executive summary: a report of the American Col-
lege of Cardiology/American Heart Association Task Force on Clini-
cal Practice Guidelines. Hypertension 2018;71(6):1269–324.
5. Bhatt H, Siddiqui M, Judd E, Oparil S, Calhoun D. Prevalence of
pseudoresistant hypertension due to inaccurate blood pressure mea-
surement. J Am Soc Hypertens 2016;10(6):493–9.
6. Wang N, Rueter P, Atkins E, et al. Efficacy and safety of low-dose
triple and quadruple combination pills vs monotherapy, usual care,
or placebo for the initial management of hypertension: a systematic
review and meta-analysis. JAMA Cardiol 2023;8(6):606–11.
7. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose
combinations improve medication compliance: a meta-analysis. Am
J Med 2007;120(8):713–9.
8. Egan BM, Zhao Y, Li J, et al. Prevalence of optimal treatment regi-
mens in patients with apparent treatment-resistant hypertension
based on office blood pressure in a community-based practice net-
work. Hypertension 2013;62(4):691–7.
9. Grigoryan L, Pavlik VN, Hyman DJ. Characteristics, drug combina-
tions and dosages of primary care patients with uncontrolled ambula-
tory blood pressure and high medication adherence. J Am Soc
Hypertens 2013;7(6):471–6.
10. Brown MA, Buddle ML, Martin A. Is resistant hypertension really
resistant? Am J Hypertens 2001;14(12):1263–9.
11. de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295
patients with resistant hypertension classified on the basis of ambula-
tory blood pressure monitoring. Hypertension 2011;57(5):898–902.
12. Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular out-
come in treated hypertensive patients with responder, masked, false
20
resistant, and true resistant hypertension. Am J Hypertens 2005;18
(11):1422–8.
13. Armario P, Calhoun DA, Oliveras A, et al. Prevalence and clinical
characteristics of refractory hypertension. J Am Heart Assoc 2017;6
(12):e007365.
14. Cardoso CRL, Salles GF. Refractory hypertension and risks of
adverse cardiovascular events and mortality in patients with resistant
hypertension: a prospective cohort study. J Am Heart Assoc 2020;9
(17):e017634.
15. Redon J, Campos C, Narciso ML, Rodicio JL, Pascual JM, Ruilope
LM. Prognostic value of ambulatory blood pressure monitoring in
refractory hypertension: a prospective study. Hypertension 1998;31
(2):712–8.
16. Salles GF, Cardoso CRL, Muxfeldt ES. Prognostic influence of office
and ambulatory blood pressures in resistant hypertension. Arch
Intern Med 2008;168(21):2340–6.
17. Berra E, Azizi M, Capron A, et al. Evaluation of adherence should
become an integral part of assessment of patients with apparently
treatment-resistant hypertension. Hypertension 2016;68(2):297–306.

18. Eskas PA, Heimark S, Eek Mariampillai J, Larstorp AC, Fadl Elmula
FE, Høieggen A. Adherence to medication and drug monitoring in
apparent treatment-resistant hypertension. Blood Press 2016;25
(4):199–205.
19. Poulter NR, Borghi C, Parati G, et al. Medication adherence in
hypertension. J Hypertens 2020;38(4):579–87.
20. Kocianova E, Taborsky M, Vaclavik J. A practical approach to
assessment of non-adherence to antihypertensive treatment. J Hyper-
tens 2023;41(9):1371–5.
21. Garfield S, Clifford S, Eliasson L, Barber N, Willson A. Suitability of
measures of self-reported medication adherence for routine clinical
use: a systematic review. BMC Med Res Methodol 2011;11:149.
22. Meddings J, Kerr EA, Heisler M, Hofer TP. Physician assessments of
medication adherence and decisions to intensify medications for
patients with uncontrolled blood pressure: still no better than a coin
toss. BMC Health Serv Res 2012;12:270.
23. Kocianova E, Vaclavık J, Tomkova J, et al. Heart rate is a useful
marker of adherence to beta-blocker treatment in hypertension.
Blood Press 2017;26(5):311–8.
24. Pandey A, Raza F, Velasco A, et al. Comparison of Morisky Medica-
tion Adherence Scale with therapeutic drug monitoring in apparent
treatment-resistant hypertension. J Am Soc Hypertens 2015;9
(6):420–426.e2.
25. Gallagher BD, Muntner P, Moise N, Lin JJ, Kronish IM. Are two
commonly used self-report questionnaires useful for identifying anti-
hypertensive medication nonadherence? J Hypertens 2015;33
(5):1108–13.
26. Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of
medication adherence and persistence using automated databases. Phar-
macoepidemiol Drug Saf 2006;15(8):565–74 [discussion 575-577.
27. El Alili M, Vrijens B, Demonceau J, Evers SM, Hiligsmann M. A
scoping review of studies comparing the medication event monitor-
ing system (MEMS) with alternative methods for measuring medica-
tion adherence. Br J Clin Pharmacol 2016;82(1):268–79.
28. Bunker J, Callister W, Chang C, Sever PS. How common is true
resistant hypertension? J Hum Hypertens 2011;25(2):137–40.
29. Fadl Elmula FE, Hoffmann P, Fossum E, et al. Renal sympathetic
denervation in patients with treatment-resistant hypertension after
witnessed intake of medication before qualifying ambulatory blood
pressure. Hypertension 2013;62(3):526–32.
30. Fadl Elmula FE, Hoffmann P, Larstorp AC, et al. Adjusted drug
treatment is superior to renal sympathetic denervation in patients
with true treatment-resistant hypertension. Hypertension 2014;63
(5):991–9.
31. Hameed MA, Tebbit L, Jacques N, Thomas M, Dasgupta I. Non-
adherence to antihypertensive medication is very common among
resistant hypertensives: results of a directly observed therapy clinic.
J Hum Hypertens 2016;30(2):83–9.
Descargado para Anonymous User (n/a) en University Hospital October 12th de ClinicalKey.es por Elsevier en enero 10, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
The American Journal of Medicine, Vol 137, No 1, January 2024
32. Hafezi H, Robertson TL, Moon GD, Au-Yeung K, Zdeblick MJ, Sav-
age GM. An ingestible sensor for measuring medication adherence.
IEEE Trans Biomed Eng 2015;62(1):99–109.
33. Ceral J, Habrdova V, Vorisek V, Bima M, Pelouch R, Solar M. Diffi-
cult-to-control arterial hypertension or uncooperative patients? the
assessment of serum antihypertensive drug levels to differentiate
non-responsiveness from non-adherence to recommended therapy.
Hypertens Res 2011;34(1):87–90.
34. Strauch B, Petrak O, Zelinka T, et al. Precise assessment of noncom-
pliance with the antihypertensive therapy in patients with resistant
hypertension using toxicological serum analysis. J Hypertens
2013;31(12):2455–61.
35. Jung O, Gechter JL, Wunder C, et al. Resistant hypertension? Assess-
ment of adherence by toxicological urine analysis. J Hypertens
2013;31(4):766–74.
36. Brinker S, Pandey A, Ayers C, et al. Therapeutic drug monitoring
facilitates blood pressure control in resistant hypertension. J Am Coll
Cardiol 2014;63(8):834–5.
37. Tomaszewski M, White C, Patel P, et al. High rates of non-adherence
to antihypertensive treatment revealed by high-performance liquid
chromatography-tandem mass spectrometry (HP LC-MS/MS) urine
analysis. Heart 2014;100(11):855–61.
38. Florczak E, Tokarczyk B, Warcho»-Celinska E, et al. Assessment of
adherence to treatment in patients with resistant hypertension using
toxicological serum analysis. A subgroup evaluation of the RESIST-
POL study. Pol Arch Med Wewn 2015;125(1-2):65–72.
39. Ewen S, Meyer MR, Cremers B, et al. Blood pressure reductions fol-
lowing catheter-based renal denervation are not related to improve-
ments in adherence to antihypertensive drugs measured by urine/
plasma toxicological analysis. Clin Res Cardiol 2015;104(12):
1097–105.
40. Patel P, Gupta PKC, White CMJ, Stanley AG, Williams B, Tomas-
zewski M. Screening for non-adherence to antihypertensive treat-
ment as a part of the diagnostic pathway to renal denervation. J Hum
Hypertens 2016;30(6):368–73.
41. Schmieder RE, Ott C, Schmid A, et al. Adherence to antihyperten-
sive medication in treatment-resistant hypertension undergoing renal
denervation. J Am Heart Assoc 2016;5(2):e002343.
42. Hamdidouche I, Jullien V, Boutouyrie P, Billaud E, Azizi M, Laurent
S. Routine urinary detection of antihypertensive drugs for systematic
evaluation of adherence to treatment in hypertensive patients. J
Hypertens 2017;35(9):1891–8.
43. Pucci M, Martin U. Detecting non-adherence by urine analysis in
patients with uncontrolled hypertension: rates, reasons and reactions.
J Hum Hypertens 2017;31(4):253–7.

44. Gupta P, Patel P, Strauch B, et al. Risk factors for nonadherence to
antihypertensive treatment. Hypertension 2017;69(6):1113–20.
45. Georges CMG, Devresse A, Ritscher S, et al. Adherence to antihy-
pertensive drug treatment in kidney transplant recipients. Blood
Press 2021;30(6):411–5.
46. Peeters LEJ, Hesselink DA, Lafeber M, et al. Monitoring antihyper-
tensive drug concentrations to determine nonadherence in hyperten-
sive patients with or without a kidney transplant. J Hypertens
2023;41(8):1239–44.
47. Gupta P, Patel P, Strauch B, et al. Biochemical screening for nonad-
herence is associated with blood pressure reduction and improvement
in adherence. Hypertension 2017;70(5):1042–8.
48. Judd E, Calhoun DA. Apparent and true resistant hypertension: Defini-
tion, prevalence and outcomes. J Hum Hypertens 2014;28(8):463–8.
49. Noubiap JJ, Nansseu JR, Nyaga UF, Sime PS, Francis I, Bigna JJ.
Global prevalence of resistant hypertension: a meta-analysis of data
from 3.2 million patients. Heart 2019;105(2):98–105.
50. Carey RM, Sakhuja S, Calhoun DA, Whelton PK, Muntner P. Preva-
lence of apparent treatment-resistant hypertension in the united
states. Hypertension 2019;73(2):424–31.
51. Chun K, Lee CJ, Oh J, et al. Prevalence and prognosis of the 2018 vs
2008 AHA definitions of apparent treatment-resistant hypertension
Filippone et al Controversies in Hypertension V: Resistant and Refractory Hypertension
in high-risk hypertension patients. J Clin Hypertens (Greenwich).
2020;22(11):2093–102.
52. Ebinger JE, Gluckman TJ, Magraner J, et al. Characterization of individ-
uals with apparent resistant hypertension using contemporary guidelines:
insights from CV-QUIC. Hypertension 2023;80(9):1845–55.
53. Holecki M, Du»awa J, Chudek J. Resistant hypertension in visceral
obesity. Eur J Intern Med 2012;23(7):643–8.
54. Demede M, Pandey A, Zizi F, et al. Resistant hypertension and
obstructive sleep apnea in the primary-care setting. Int J Hypertens
2011;2011:340929.
55. Acharya T, Tringali S, Singh M, Huang J. Resistant hypertension and
associated comorbidities in a veterans affairs population. J Clin
Hypertens (Greenwich) 2014;16(10):741–5.
56. Fay KS, Cohen DL. Resistant hypertension in people with CKD: a
review. Am J Kidney Dis 2021;77(1):110–21.
57. Buhnerkempe MG, Prakash V, Botchway A, et al. Adverse health
outcomes associated with refractory and treatment-resistant hyper-
tension in the chronic renal insufficiency cohort. Hypertension
2021;77(1):72–81.
58. Cuspidi C, Macca G, Sampieri L, et al. High prevalence of cardiac
and extracardiac target organ damage in refractory hypertension. J
Hypertens 2001;19(11):2063–70.
59. Oliveras A, Armario P, Hernandez-Del Rey R, et al. Urinary albumin
excretion is associated with true resistant hypertension. J Hum
Hypertens 2010;24(1):27–33.
60. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis
of resistant hypertension in hypertensive patients. Circulation
2012;125(13):1635–42.
61. Bacan G, Ribeiro-Silva A, Oliveira VAS, Cardoso CRL, Salles GF.
Refractory hypertension: a narrative systematic review with empha-
sis on prognosis. Curr Hypertens Rep 2022;24(4):95–106.
62. Taler SJ, Textor SC, Augustine JE. Resistant hypertension: compar-
ing hemodynamic management to specialist care. Hypertension
2002;39(5):982–8.
63. Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized preva-
lence of primary aldosteronism: a cross-sectional study. Ann Intern
Med 2020;173(1):10–20.
64. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann
P. Hyperaldosteronism among black and white subjects with resistant
hypertension. Hypertension 2002;40(6):892–6.
65. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characteri-
zation of resistant hypertension: association between resistant hyper-
tension, aldosterone, and persistent intravascular volume expansion.
Arch Intern Med 2008;168(11):1159–64.
66. Freeman MW, Halvorsen Y, Marshall W, et al. Phase 2 trial of bax-
drostat for treatment-resistant hypertension. N Engl J Med 2023;388
(5):395–405.
67. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun
DA. Refractory hypertension: evidence of heightened sympathetic
activity as a cause of antihypertensive treatment failure. Hyperten-
sion 2015;66(1):126–33.
68. Velasco A, Siddiqui M, Kreps E, et al. Refractory hypertension is not
attributable to intravascular fluid retention as determined by intracar-
diac volumes. Hypertension 2018;72(2):343–9.
69. Dahal K, Kunwar S, Rijal J, et al. The effects of aldosterone antagonists
in patients with resistant hypertension: A meta-analysis of randomized
and nonrandomized studies. Am J Hypertens 2015;28(11):1376–85.
70. Guo H, Xiao Q. Clinical efficacy of spironolactone for resistant
hypertension: a meta analysis from randomized controlled clinical
trials. Int J Clin Exp Med 2015;8(5):7270–8.
71. Liu G, Zheng XX, Xu YL, Lu J, Hui RT, Huang XH. Effect of aldo-
sterone antagonists on blood pressure in patients with resistant hyper-
tension: a meta-analysis. J Hum Hypertens 2015;29(3):159–66.
72. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus
placebo, bisoprolol, and doxazosin to determine the optimal treat-
ment for drug-resistant hypertension (PATHWAY-2): a randomised,
double-blind, crossover trial. Lancet 2015;386(10008):2059–68.
Descargado para Anonymous User (n/a) en University Hospital October 12th de ClinicalKey.es por Elsevier en enero 10, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
21
73. Sinnott S, Tomlinson LA, Root AA, et al. Comparative effectiveness
of fourth-line anti-hypertensive agents in resistant hypertension: a
systematic review and meta-analysis. Eur J Prev Cardiol 2017;24
(3):228–38.
74. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. random-
ized Aldactone evaluation study investigators. N Engl J Med
1999;341(10):709–17.
75. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart fail-
ure with preserved ejection fraction. N Engl J Med 2014;370
(15):1383–92.
76. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldoste-
rone blocker, in patients with left ventricular dysfunction after myo-
cardial infarction. N Engl J Med 2003;348(14):1309–21.
77. Montalescot G, Pitt B, Lopez de Sa E, et al. Early eplerenone treat-
ment in patients with acute ST-elevation myocardial infarction with-
out heart failure: the randomized double-blind reminder study. Eur
Heart J 2014;35(34):2295–302.
78. Beygui F, Cayla G, Roule V, et al. Early aldosterone blockade in
acute myocardial infarction: the ALBATROSS randomized clinical
trial. J Am Coll Cardiol 2016;67(16):1917–27.
79. Alexandrou M, Papagianni A, Tsapas A, et al. Effects of mineralo-
corticoid receptor antagonists in proteinuric kidney disease: a sys-
tematic review and meta-analysis of randomized controlled trials. J
Hypertens 2019;37(12):2307–24.
80. Bolignano D, Palmer SC, Navaneethan SD, Strippoli G. Aldosterone
antagonists for preventing the progression of chronic kidney disease.
Cochrane Database Syst Rev 2014(4).
81. Beldhuis IE, Myhre PL, Claggett B, et al. Efficacy and safety of spi-
ronolactone in patients with HFpEF and chronic kidney disease.
JACC Heart Fail 2019;7(1):25–32.
82. Chung EY, Ruospo M, Natale P, et al. Aldosterone antagonists in
addition to renin angiotensin system antagonists for preventing the
progression of chronic kidney disease. Cochrane Database Syst Rev
2020;10(10):CD007004.
83. Rossignol P, Massy ZA, Azizi M, et al. The double challenge of
resistant hypertension and chronic kidney disease. Lancet 2015;386
(10003):1588–98.
84. Agarwal R, Rossignol P, Romero A, et al. Patiromer versus pla-
cebo to enable spironolactone use in patients with resistant
hypertension and chronic kidney disease (AMBER): a phase 2,
randomised, double-blind, placebo-controlled trial. Lancet
2019;394(10208):1540–50.
85. Agarwal R, Rossignol P, Mayo MR, et al. Patiromer to enable spiro-
nolactone in patients with resistant hypertension and CKD
(AMBER): results in the prespecified subgroup with diabetes. Clin J
Am Soc Nephrol 2021;16(9):1407–9.
86. Rossignol P, Williams B, Mayo MR, et al. Patiromer versus placebo
to enable spironolactone use in patients with resistant hypertension
and chronic kidney disease (AMBER): results in the pre-specified
subgroup with heart failure. Eur J Heart Fail 2020;22(8):1462–71.
87. Koca D, Lother A. Molecular pharmacology of mineralocorticoid
receptor antagonists: the role of co-regulators. Steroids
2023;199:109291.
88. Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal
mineralocorticoid receptor antagonists in cardiorenal medicine. Eur
Heart J 2021;42(2):152–61.
89. Lo KB, Rangaswami J, Vaduganathan M. Non-steroidal mineralo-
corticoid receptor antagonists and cardiorenal outcomes in chronic
kidney disease. Nephrol Dial Transplant 2023;38(4):845–54.
90. Ito S, Itoh H, Rakugi H, Okuda Y, Yamakawa S. Efficacy and safety
of esaxerenone (CS-3150) for the treatment of essential hyperten-
sion: a phase 2 randomized, placebo-controlled, double-blind study.
J Hum Hypertens 2019;33(7):542–51.
91. Bakris G, Pergola PE, Delgado B, et al. Effect of KBP-5074 on blood
pressure in advanced chronic kidney disease: results of the BLOCK-
CKD study. Hypertension 2021;78(1):74–81.
22
92. Bakris GL, Yang YF, McCabe JM, et al. Efficacy and safety of oce-
durenone: subgroup analysis of the BLOCK-CKD study. Am J
Hypertens 2023.
93. Agarwal R, Pitt B, Palmer BF, et al. A comparative post hoc analysis
of finerenone and spironolactone in resistant hypertension in moder-
ate-to-advanced chronic kidney disease. Clin Kidney J 2022;16
(2):293–302.
94. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the
novel non-steroidal mineralocorticoid receptor antagonist BAY 94-
8862 in patients with chronic heart failure and mild or moderate
chronic kidney disease: a randomized, double-blind trial. Eur Heart
J 2013;34(31):2453–63.
95. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albu-
minuria in patients with diabetic nephropathy: a randomized clinical
trial. JAMA 2015;314(9):884–94.
96. Katayama S, Yamada D, Nakayama M, et al. A randomized con-
trolled study of finerenone versus placebo in Japanese patients with
type 2 diabetes mellitus and diabetic nephropathy. J Diabetes Com-
plications 2017;31(4):758–65.
97. Ito S, Shikata K, Nangaku M, Okuda Y, Sawanobori T. Efficacy and
safety of esaxerenone (CS-3150) for the treatment of type 2 diabetes
with microalbuminuria: a randomized, double-blind, placebo-con-
trolled, phase II trial. Clin J Am Soc Nephrol 2019;14(8):1161–72.
98. Ito S, Kashihara N, Shikata K, et al. Esaxerenone (CS-3150) in
patients with type 2 diabetes and microalbuminuria (ESAX-DN):
phase 3 randomized controlled clinical trial. Clin J Am Soc Nephrol
2020;15(12):1715–27.
99. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on
chronic kidney disease outcomes in type 2 diabetes. N Engl J Med
2020;383(23):2219–29.
100. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with
finerenone in kidney disease and type 2 diabetes. N Engl J Med
2021;385(24):2252–63.
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The American Journal of Medicine, Vol 137, No 1, January 2024
101. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney out-
comes with finerenone in patients with type 2 diabetes and chronic
kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022;43
(6):474–84.
102. Sarafidis P, Agarwal R, Pitt B, et al. Outcomes with finerenone in
participants with stage 4 CKD and type 2 diabetes: a FIDELITY sub-
group analysis. Clin J Am Soc Nephrol 2023;18(5):602–12.
103. Ahmed M, Nudy M, Bussa R, Naccarelli GV, Filippone EJ, Foy AJ.
A subgroup meta-analysis comparing the renal denervation sham-
controlled randomized trials among those with resistant and nonresis-
tant hypertension. Am J Cardiol 2023;191:119–24.
104. Siddiqui M, Bhatt H, Judd EK, Oparil S, Calhoun DA. Reserpine sub-
stantially lowers blood pressure in patients with refractory hypertension:
a proof-of-concept study. Am J Hypertens 2020;33(8):741–7.
105. Navarro-Soriano C, Martınez-Garcıa M, Torres G, et al. Effect of
continuous positive airway pressure in patients with true refractory
hypertension and sleep apnea: a post-hoc intention-to-treat analysis
of the HIPARCO randomized clinical trial. J Hypertens 2019;37
(6):1269–75.
106. Falkovskaya AY, Mordovin VF, Pekarskiy SE, et al. Refractory and
resistant hypertension in patients with type 2 diabetes mellitus: dif-
ferent response to renal denervation. Kardiologiia 2021;61(2):54–61.
107. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selec-
tive nonsteroidal mineralocorticoid receptor antagonist protects from
rat cardiorenal injury. J Cardiovasc Pharmacol 2014;64(1):69–78.
108. Barrera-Chimal J, Kolkhof P, Lima-Posada I, Alexandre J, Rossignol
P, Jaisser F. Differentiation between emerging non-steroidal and
established steroidal mineralocorticoid receptor antagonists: head-to-
head comparisons of pharmacological and clinical characteristics.
Expert Opin Investig Drugs 2021;30(11):1141–57.
109. Pamporaki C, Prejbisz A, Ma»ecki R, et al. Optimized reference
intervals for plasma free metanephrines in patients with CKD. Am J
Kidney Dis 2018;72(6):907–9.