Clinical Review & Education
Clinical Insights
Management of Resistant Hypertension—An Update
John M. Giacona, PA-C, PhD; Weerapat Kositanurit, MD; Wanpen Vongpatanasin, MD
Resistant hypertension (RH) is defined as having either (1) a blood
pressure (BP) of 130/80 mm Hg or more, despite maximally toler-
ated doses of 3 or more antihypertensive drugs (with at least 1 di-
uretic) or (2) controlled hypertension (HTN) with 4 or more antihy-
pertensive drugs.1 The estimated prevalence of RH was approximately
12% to 18% in population-based and clinic-based reports, with RH
rates up to 38% in clinical trials, according to the 2018 American Heart
Association scientific statement. Patients with RH also have an in-
creased risk for cardiovascular events, stroke, and all-cause mortal-
ity. The risk factors for RH include Black race, older age, male sex, obe-
sity, diabetes, and the presence of chronic kidney disease.
Before diagnosing true RH, clinicians first need to exclude the
presence of pseudo-resistant RH from medication nonadherence and
the “white coat” effect (Figure).1 The identification of the white coat
effect can be achieved by out-of-office BP monitoring.
The inconsistent use of antihypertensive drugs has been iden-
tified in 20% to 60% of patients with apparent RH.2 Practical meth-
ods to monitor adherence include patient self-report, question-
naire, and pharmacy refill report. If nonadherence is determined,
clinicians must identify potential barriers, including complex drug
regimens, medication cost, or adverse effects, and should work with
the patient to overcome the specific barriers. Therapeutic monitor-
ing of serum drug concentrations is an emerging technique avail-
able in clinical practice that is shown to be cost-effective and more
accurate than pharmacy refill reports.
Screening for secondary forms of HTN is an important step in
the evaluation of RH.1 Primary aldosteronism has been identified
in up to 20% of patients with RH, but only 20% to 50% of patients
with primary aldosteronism present with hypokalemia.3 As such, all
patients with RH should undergo primary aldosteronism screen-
ing, regardless of serum potassium, by assessing plasma renin ac-
tivity (PRA) and plasma aldosterone concentration. Screening can
be performed during treatment with mineralocorticoid receptor
antagonists (MRA), angiotensin-converting enzyme inhibitors, or
angiotensin receptor blockers. These drugs typically raise PRA, thus
the presence of suppressed PRA while taking them should increase
suspicion for primary aldosteronism. If PRA is not suppressed with
drug treatment, and there is high likelihood for primary aldosteron-
ism, repeat testing after 2 or more weeks of drug washout is rec-
ommended. Hypokalemia should be corrected to 4.0 mmol/L to
5.0 mmol/L before screening to avoid a false-negative test result.
Findings of elevated plasma aldosterone concentration (>10 ng/dL)
in the context of suppressed PRA strongly suggest the presence of
primary aldosteronism and warrant referral to HTN specialists for
additional testing (ie, salt loading test) and treatment.
Other causes of secondary RH, including obstructive sleep ap-
nea, renal artery stenosis, pheochromocytoma, Cushing syn-
drome, and medications that could raise BP (eg, nonsteroidal anti-
inflammatory drugs, exogenous steroids, and stimulants) should be
assessed based on individual patient characteristics and clinician
inclination (Figure).1
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Figure. Proposed Algorithm for Management of Resistant Hypertension
Office BP ≥130/80 mm Hg receiving ACEI (ARB) + CCB + diuretics
at maximal or maximally tolerated doses or receiving ≥4 antihypertensive
medications (regardless of BP)
Optimize diuretic: switch current diuretic to chlorthalidone unless CKD stage 5
24-h ABPM <125/75 mm Hg or home BP <130/80 mm Hg
Yes? • Consider white coat effect
• Continue home BP monitoring
No?
Assess medication adherence:
(pharmacy refill data, biochemical drug levels, ie, serum or urine)
Assess lifestyle modifications:
• Reduce dietary sodium intake <1500 mg/d
• Moderate intensity aerobic exercise of 30-45 min 3 times/wk
• Maintain healthy body weight
• Remove interfering agents (ie, NSAIDs)
Investigate for secondary causes of hypertension:
• Plasma renin activity, serum aldosterone in all resistant hypertension
• If clinically indicated: polysomnography, renal duplex Doppler
ultrasonography, CT angiogram of renal artery, thyroid function test,
24-h urinary free cortisol, plasma metanephrines
Add MRA: spironolactone, 25 mg daily (or eplerenone, 25-50 mg, twice daily
or amiloride, 10 mg daily, if eGFR >30 mL/min 1.73 m2)
Add fifth-line drug therapy:
• If HR <60 bpm: add α AR blockers (ie, doxazosin)
• If HR 60-80 bpm: add any drug from different classes
• If HR >80 bpm: add BB, nondihydropyridine CCB, or long-acting central
sympatholytic drug (ie, guanfacine)
or
• Refer to hypertension specialist
This flow diagram represents the decision process for treatment of resistant
hypertension. ABPM indicates ambulatory blood pressure monitoring;
ACEI, angiotensin-converting enzyme inhibitor; AR, adrenergic receptor;
ARB, angiotensin receptor blocker; BB, β-blocker; BP, blood pressure;
CCB, calcium channel blocker; CKD, chronic kidney disease; CT, computed
tomography; eGFR, estimated glomerular filtration rate; HR, heart rate;
MRA, mineralocorticoid receptor antagonists; NSAID, nonsteroidal
anti-inflammatory drug.
First-line treatment for RH should focus on lowering sodium
intake to less than 1500 mg/d and engaging in moderate-intensity
exercise for at least 150 min/wk, which have each been shown to
reduce systolic blood pressure (SBP) by up to 10 mm Hg among
patients with RH.1,4
If secondary causes have been identified, treatments specific
to the cause should be implemented. For primary aldosteronism,
surgical adrenalectomy should be considered in unilateral cases,
as it is shown to cure HTN in 10% to 20% of patients, while bilat-
eral primary aldosteronism should be treated with MRA.5 For
(Reprinted) JAMA Internal Medicine Published online February 19, 2024 E1
 Clinical Review & Education Clinical Insights

those found to have obstructive sleep apnea, research has demon-
strated that patients with RH undergoing treatment with continu-
ous positive airway pressure experience a 2– to 5–mm Hg reduc-
tion in SBP.1 Additionally, weight loss has been shown to reduce
BP in RH.
For patients whose BP remains uncontrolled despite guideline-
directed antihypertensive therapy, consider switching the diuretic
to long-acting chlorthalidone (if estimated glomerular filtration rate
[eGFR] > 30 mL/min/1.73 m2) or a long-acting loop diuretic such as
torsemide (if eGFR < 30 mL/min/1.73 m2).1 If BP remains elevated,
consider adding an MRA such as spironolactone (if eGFR > 30 mL/
min/1.73 m2) as the fourth-line medication. Eplerenone or amiloride
can be used as alternatives in patients with adverse effects to spi-
ronolactone. Selection of a fifth-line medication is often dictated by
patient features such as resting heart rate (HR). β-Blocker or anti-
hypertensive agents that slow HR should be avoided in patients with
bradycardia or heart block or patients with isolated systolic HTN
because greater stroke volume is required to maintain cardiac out-
put. Vasodilating agents, such as α-blockers (eg, doxazosin), may
reduce BP while promoting reflex tachycardia. In the presence of el-
evated HR, β-blockers, nondihydropyridine calcium channel block-
ers (eg, verapamil), or central sympatholytic medications (eg, gua-
nfacine or transdermal clonidine) are suitable as fifth-line drugs. For
patients with RH and anxiety or depressive symptoms that may be
sympathetically driven, it is reasonable to consider a selective sero-
tonin reuptake inhibitor. If BP remains uncontrolled after initiation
of the fourth-line or fifth-line agent, referral to an HTN specialist is
recommended.
In an observational study of more than 1700 Black patients with
RH, lifestyle factors, including smoking status, alcohol consump-
tion, physical activity, and body mass index, were reported, as well
as the proportion taking recommended antihypertensive medica-
tions (ie, thiazidelike diuretics, such as chlorthalidone, and MRAs)
were reported.6 Among Black adults with RH, less than 15% had ideal
levels of 3 of 4 lifestyle factors, with less than 2% having ideal lev-
els of all 4. Socioeconomic barriers, such as inequitable access to
health care and healthy foods, can help to explain this racial dispar-
ity. Furthermore, less than 10% of Black adults with RH in the study
were estimated to receive thiazidelike diuretics or an MRA. Health
systems reform, investment in health-focused infrastructure within
Black communities, and clinician education are needed to reduce
health disparities in RH.
Several novel therapies are being studied for the treatment of
RH. Aldosterone synthase inhibitors, such as baxdrostat and lorun-
drostat, have been shown to induce a sustained reduction in serum
aldosterone levels and BP in uncontrolled HTN independent of
PRA.7 Zilebesiran, another novel agent that inhibits the renin-
angiotensin system by suppressing hepatic angiotensinogen pro-
duction, induced a sustained reduction in BP up to 6 months after
a single injection.8 However, the BP-lowering effect of zilebesiran
was attenuated with a high-sodium diet. Aprocitentan, a dual en-
dothelin antagonist, was shown to be effective in patients with RH
in a phase 3 randomized clinical trial.9 The ultrasound renal dener-
vation system was also shown to be effective in reducing daytime
ambulatory SBP by 4.5 mm Hg in patients with RH compared with
the sham-controlled study group.10 Additionally, the presence of or-
thostatic HTN and elevated HR were associated with greater BP re-
sponses to renal denervation. Assessment of these factors may be
important in selecting candidates for novel therapies in RH.
RH is a complex disorder with several contributing factors and
potential secondary causes. Successful treatment of RH requires a
combination of both pharmacologic and nonpharmacologic inter-
ventions. Emerging treatments are being developed which will in-
crease therapeutic options. However, disparities in the manage-
ment of RH remain a challenge, and a concerted approach is
necessary to promote equitable health-related outcomes.

ARTICLE INFORMATION
Author Affiliations: Hypertension Section,
Cardiology Division, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas (Giacona, Kositanurit,
Vongpatanasin); Department of Applied Clinical
Research, School of Health Professions, University
of Texas Southwestern Medical Center, Dallas
(Giacona); Department of Physiology, Faculty of
Medicine, Chulalongkorn University, Bangkok,
Thailand (Kositanurit).
Corresponding Author: Wanpen Vongpatanasin,
MD, Hypertension Section, Cardiology Division,
Department of Internal Medicine, University of
Texas Southwestern Medical Center,
5323 Harry Hines Blvd, Dallas, TX 75390-8586
(wanpen.vongpatanasin@utsouthwestern.edu).
Published Online: February 19, 2024.
doi:10.1001/jamainternmed.2023.8555
Conflict of Interest Disclosures: None reported.
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