REVIEW CME MOC

Jordana Yahr, DO George Thomas, MD Juan Calle, MD Jonathan J. Taliercio, DO

Department of Internal Medicine, Cleveland Director, Center for Blood Pressure Disorders, Department of Kidney Medicine, Glickman Program Director, Nephrology and Hyper-
Clinic, Cleveland, OH Department of Kidney Medicine, Glickman Urological and Kidney Institute Cleveland tension Fellowship, Department of Kidney
Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; Clinical Assistant Medicine, Glickman Urological and Kidney
Clinic, Cleveland, OH; Associate Professor, Professor, Cleveland Clinic Lerner College of Institute, Cleveland Clinic, Cleveland, OH;
Cleveland Clinic Lerner College of Medicine Medicine of Case Western Reserve University, Associate Professor, Cleveland Clinic Lerner
of Case Western Reserve University, Cleveland, OH College of Medicine of Case Western Reserve
Cleveland, OH; Co-principal Investigator University, Cleveland, OH; Co-principal
for SPRINT and SYMPLICITY HTN-3 Investigator for SYMPLICITY HTN-3

Resistant hypertension:
A stepwise approach
ABSTRACT ost patients with hypertension do not
Resistant hypertension can be challenging to manage,
M achieve current recommended blood
pressure targets. It is imperative that physicians
but a stepwise approach to diagnosis, evaluation, and recognize risk factors associated with resistant
treatment can lead to better blood pressure control. In hypertension in order to better control it. In this
this article, we review the definition and prevalence of article, we discuss the epidemiology, diagnosis,
resistant hypertension and its diagnostic workup and evaluation, and treatment of resistant hyper-
management, including lifestyle modifications, drugs, tension and a stepwise approach (Figure 1)1,2 to
and experimental interventional therapies. getting patients to their goal blood pressure.

KEY POINTS ■ MOVING THE GOALPOST: HYPERTENSION

IS NOW 130/80 MM HG OR HIGHER
Owing to stricter definitions and targets in the 2017
guidelines than in earlier guidelines, the prevalence of The 2017 American College of Cardiology
hypertension and resistant hypertension has increased. (ACC) and American Heart Association
(AHA) guidelines define hypertension as systolic
Patients with resistant hypertension are at higher risk of blood pressure 130 mm Hg or higher or diastolic
complications including cardiovascular disease, stroke, blood pressure 80 mm Hg or higher, based on at
kidney failure, and death. least 2 readings obtained on at least 2 occasions.1
This is stricter than the 2003 guidelines
It is important to identify common factors that contribute from the Seventh Joint National Committee
to resistant hypertension to mitigate their effects. Hyper- on Detection, Evaluation, and Treatment of
High Blood Pressure,3 which defined hyper-
tensive patients who have resistant hypertension should
tension as blood pressure 140/90 mm Hg or
undergo evaluation for secondary causes. higher. As a result of the new definition, the
prevalence of hypertension in the United
Along with lifestyle modification, a stepwise approach States increased from roughly 32% to 47%.4
to management using antihypertensive medications with Hypertension is a leading cause of cardio-
differing mechanisms of action is critical to achieving vascular disease and death.5 Its management
blood pressure control. Patients may require more anti- costs the US healthcare system approximately
hypertensive medications. $131 billion annually.6

■ GOAL IS INDIVIDUALIZED,
BUT LESS THAN 130/80 FOR MOST
Blood pressure targets should be individualized
based on patient characteristics, medication
doi:10.3949/ccjm.90a.22046 side effects, patient tolerance, and preferences.

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RESISTANT HYPERTENSION

Office blood pressure above goal on at least 3 antihypertensive medications

 (typically ACEi or ARB, diuretic, and calcium channel blocker

Confirm with out-of-office monitoring (ABPM or SMBP)

Stop medications that

Reinforce lifestyle may potentially inter-
modifications such as fere with blood pres-
Review and assess low-sodium DASH diet, sure control, including Consider evaluation for Exclude secondary
medication adherence weight management, NSAIDs, OCPs, nasal obstructive sleep apnea causes of  hypertension
physical activity, and decongestants, herbal
limiting alcohol use supplements contain-
ing licorice, and illicit
substances

Optimize medications including dosing at maximal or maximally tolerated doses

Chlorthalidone or indapamide are preferred thiazide-like diuretics
Short-acting loop diuretics should be dosed at least twice daily
Avoid dual ACEi/ARB therapy

Add MRA (spironolactone preferred, eplerenone if not tolerated)

Additional agents:

Vasodilatory beta-blockers are first-line therapy if compelling indications are present

Central alpha-receptor agonists such as clonidine patch or guanfacine,

a longer-acting agent

Alpha-receptor antagonists such as prazosin, doxazosin, or terazosin

Vasodilators hydralazine or minoxidil 

Refers to guideline recommendations

with evidentiary support

Refers to therapy to be individualized

to the patient

Figure 1. Management of resistant hypertension, recommendations adapted from the American Heart
Association scientific statement on resistant hypertension, reference 2.
ABPM = ambulatory blood pressure monitoring; ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; DASH = Dietary Approaches
to Stop Hypertension; MRA = mineralocorticoid receptor antagonist; NSAIDs = nonsteroidal anti-inflammatory drugs; OCPs = oral contraceptive pills;
SMBP = self-measured blood pressure

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 YAHR AND COLLEAGUES

In patients with cardiovascular disease or with Pseudoresistance is suboptimal blood pressure con-
a risk of an atherosclerotic cardiovascular disease trol secondary to medication nonadherence, white-
event of 10% or higher in the next 10 years, the 2017 coat effect, or poor measurement technique.
ACC-AHA guidelines say that a goal of less than Apparent treatment-resistant hypertension is the term
130/80 mm Hg “is recommended.”1 used in epidemiologic studies to refer to cases in which
In patients at lower risk, the ACC-AHA guide- patients meet the criteria for resistant hypertension
lines say the same goal “may be reasonable.”1 but have unverified adherence or medication dosing
In patients with chronic kidney disease, the or have not undergone out-of-office blood pressure
2021 Kidney Disease Improving Global Outcomes monitoring to rule out the white-coat effect.
guidelines recommended keeping the systolic blood
pressure lower than 120 mm Hg contingent on ■ PREVALENCE AND PROGNOSIS
proper blood pressure measurement.7 This recom-
The prevalence of resistant hypertension is diffi-
mendation is based largely on the cardiovascular
cult to ascertain precisely, given the need to rule
benefits of this lower goal demonstrated in the Sys-
out pseudoresistance. However, an estimate from
tolic Blood Pressure Intervention Trial,8 in which
the National Health and Nutrition Examination
patients at risk of cardiovascular disease but without
Survey (NHANES) put the prevalence of apparent
diabetes were randomized to goal blood pressures of
treatment-resistant hypertension (using the cutoff of
either less than 120 mm Hg or less than 140 mm
≥ 140/90 mm Hg) in the general public at 12.8%.12
Hg. In a chronic kidney disease subgroup analy-
In hypertensive patients in the Chronic Renal Insuf-
sis, the intensive group had a slightly higher rate
ficiency Cohort, the prevalence of apparent treat-
of change in estimated glomerular filtration rate
ment-resistant hypertension using the same definition
(−0.47 vs −0.32 mL/min/1.73 m2 per year; P < .03) was 40.4%.13 Other comorbidities associated with
after 6 months. The decline in kidney function may resistant hypertension include older age, obesity, dia-
be hemodynamically mediated as a result of more betes mellitus, and obstructive sleep apnea.14,15
intensive blood pressure control.8,9
In patients with diabetes, the American Diabe-
tes Association recommends a target blood pressure Of the 116 million Americans with hypertension,
lower than 130/80 mm Hg.10 only 23.9 million (20.6%) have their blood
Most people are not meeting these goals. Accord-
ing to an estimate from the US Centers for Disease pressure controlled using the 2017 ACC-AHA
Control and Prevention, of the 116 million Ameri- definitions
cans with hypertension, only 23.9 million (20.6%)
have their blood pressure controlled using the 2017 Resistant hypertension is associated with worse
ACC-AHA definitions.11 The control rate was outcomes, particularly adverse kidney outcomes and
62.8% using the old threshold of less than 140/90 cardiovascular morbidity and death.14–16 In a study of
mm Hg.11 10,001 patients, apparent treatment-resistant hyper-
tension was associated with a 64% higher incidence
■ RESISTANCE, PSEUDORESISTANCE, of the composite cardiovascular outcome of fatal cor-
OR APPARENT RESISTANCE? onary heart disease, nonfatal myocardial infarction,
cardiac arrest, and stroke.16 Apparent treatment-re-
Resistant hypertension is defined by the ACC-
sistant hypertension was shown to increase the risk of
AHA as blood pressure that is above goal despite
kidney failure in an analysis of participants from the
the patient receiving at least 3 medications with
Antihypertensive and Lipid-Lowering Treatment to
different mechanisms of action. All medications
Prevent Heart Attack Trial (hazard ratio 1.95; 95%
must be prescribed at maximally tolerated doses
confidence interval 1.11–3.41).15
and should preferably include a long-acting dihy-
dropyridine calcium channel blocker, either an ■ DIAGNOSIS OF RESISTANT HYPERTENSION
angiotensin-converting enzyme (ACE) inhibitor
or an angiotensin II receptor blocker (ARB), and The diagnosis of resistant hypertension requires
a diuretic. Resistant hypertension is also defined as ruling out pseudoresistance due to medication non-
controlled blood pressure on at least 4 antihyper- adherence, improper blood pressure measurement,
tensive medications.2 and the white-coat effect.
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RESISTANT HYPERTENSION

TABLE 1
Proper blood pressure measurement
Patients should sit, relaxed, for at least 5 minutes, with an empty bladder, without talking; they should not have consumed caffeine, smoked,
or exercised in the last 30 minutes.
Use a device that has been properly calibrated, and a proper-sized cuff: the bladder should wrap around 80% of the patient’s arm; a small cuff
will result in higher blood pressure readings.

Take measurements in both arms, on bare skin, with the patient’s arm supported; use the arm with the higher reading for subsequent
readings, and repeat measurements 1 to 2 minutes apart.

Use the average of at least 2 readings obtained on at least 2 occasions to estimate blood pressure.

Based on information in reference 1.

Is the patient taking the medication? Sources of inaccuracy with auscultatory blood
Medication nonadherence is a discrepancy between pressure measurement include inadequate operator
how a medication is prescribed and how the patient is skill, inability to hear Korotkoff sounds, and terminal
actually taking it.2 Its prevalence in patients with appar- digit bias. If you measure blood pressure using the aus-
ent treatment-resistant hypertension is difficult to deter- cultatory technique, you should pay careful attention
mine. Studies have shown it ranging from 3% to 86%, to operator training, proper cuff size, and technique.
with a pooled estimate of 31% in a meta-analysis.17 Aneroid sphygmomanometers require more frequent
Medication adherence can also be difficult to calibration than oscillatory machines.
address, but several techniques have been studied.18,19 What is the patient’s blood pressure out of the office?
Some laboratories offer serum and urine assays to detect Current guidelines recommend measuring blood pres-
metabolites of antihypertensive drugs, and pharma- sure out of the office to complement in-office mea-
cy-based assessments include pharmacy fill history and surement to control hypertension, but not as the sole
pill counting.18 Directly observed therapy has been measurement.1,7 It can improve diagnostic accuracy
shown to reduce resistant hypertension by 29%.19 Each and help detect other forms of hypertension such as
of these methods has limitations such as inaccuracies white-coat or masked hypertension (see discussion
in patient reporting and physician interviewing, as below). Two monitoring methods are used: ambula-
well as the impracticality and cost of directly observing tory and self-measured.
therapy or measuring drug metabolites. Self-measurement means the patient takes their
Ensuring that patients understand their medica- blood pressure at regular times during the day.22 While
tion instructions and involving them in shared deci- there is no consensus on the optimal schedule for
sion-making are important to improve adherence.20 checking blood pressure at home, 2 to 3 consecutive
measurements can be performed twice daily in the
Are the measurements accurate? morning and evening, for a minimum of 3 and ideally
Measuring blood pressure accurately requires proper 5 to 7 consecutive days every month. We recommend
technique, proper cuff size, and use of validated measuring blood pressure before taking antihyperten-
devices (Table 1).1 sive medications to better assess control.
Automated office blood pressure monitoring Ambulatory monitoring records blood pressure
devices are favored over conventional manual aus- over a 24-hour period. An advantage is its ability to
cultatory devices for office use.1,7 These devices are measure nocturnal blood pressure. Blood pressure nor-
designed to take multiple blood pressure readings in mally dips by 10% to 20% during sleep, and patients
one sitting. who are “nondippers” are at higher risk of cardiovas-
In one study, the mean systolic blood pressure cular events.22
taken by automated office blood pressure devices was White-coat hypertension is elevated in-office blood
11 mm Hg lower than those obtained with manual pressure readings with normal out-of-office blood
in-office devices, and the results from in-office auto- pressure in a person not being treated with antihy-
mated devices were more consistent with those of pertensive medication (Table 2).7 In contrast, the
ambulatory blood pressure monitoring.21 white-coat effect is the same pattern in a person who
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 YAHR AND COLLEAGUES

TABLE 2
Patterns of in-office and out-of-office blood pressure in treated hypertension
Out-of-office blood pressure
(by daytime ambulatory or home blood pressure monitoring)

Normal Higha
a
In-office blood pressure High White-coat effect Uncontrolled hypertension

Normal Controlled hypertension Masked uncontrolled hypertension

a
Blood pressure 130/80 mm Hg or higher.
Adapted from information in reference 7.

is receiving treatment for hypertension.23 The white- without obesity. This effect was not seen in men.
coat effect may be seen in 28% to 39% of those with However, there are currently no blood pressure guide-
resistant hypertension.2 lines that have specific medication recommendations
Untreated white-coat hypertension is associated for patients with obesity vs nonobesity.
with a higher risk of cardiovascular events compared
with sustained normotension.23 In contrast, in a The amount of sodium in the diet
recent meta-analysis, patients with the white-coat Dietary sodium increases blood pressure.28 This effect
may not occur in all people, but certain groups are
effect (ie, on treatment, with normal blood pressures
more salt-sensitive, including older adults, Black peo-
at home but high blood pressure in the office) showed
ple, and patients with chronic kidney disease.1
no increase in cardiovascular risk compared with
In a randomized crossover trial in 12 patients with
those with controlled hypertension.24
resistant hypertension, reducing dietary sodium from
Masked hypertension is normal office blood pressure
250 mmol/day (5,750 mg) per day for 1 week to 50
readings but elevated out-of-office readings. Patients
mmol (1,150 mg) per day for 1 week lowered office sys-
with masked hypertension are at higher risk of cardio-
tolic blood pressure by 22.7 mm Hg (95% confidence
vascular events than normotensive patients or those
interval –33.5 to –11.8; P = .008).29 Patients with resis-
with white-coat hypertension.24
tant hypertension had more significant blood pressure
reductions than other patients with hypertension or
■ DOES THE PATIENT HAVE LIFESTYLE FACTORS
the general population, suggesting salt sensitivity may
THAT RAISE BLOOD PRESSURE?
play a bigger role in the pathogenesis of resistant hyper-
tension and reinforcing the importance of including a
Obesity diuretic in the treatment plan.
The relationship between increased adiposity and Patients should be counseled to adhere to a diet
elevated blood pressure has been well established.25 with less than 2 g of sodium per day (5 g of table salt)
NHANES participants who had a body mass index in addition to the DASH (Dietary Approaches to
of 30 kg/m2 or higher were twice as likely to have resistant Stop Hypertension) diet, which is low in sodium and
or apparent treatment-resistant hypertension.12,26 rich in fruit, vegetables, and low-fat dairy products,
Pathogenic mechanisms of obesity-related hyper- as the combination of these 2 was shown to be more
tension include increased salt sensitivity, increased effective than either alone.28
sympathetic nervous system activity, activation of the
renin-angiotensin-aldosterone system, and aldosterone Recommended exercise
secretion by adipose tissue.25 Of these mechanisms, Aerobic exercise has been shown to reduce blood
aldosterone secretion by adipose tissue is the only one pressure in patients with hypertension and resistant
that is obesity-specific, as the others can also occur in hypertension.30 Patients with resistant hypertension
diseases such as chronic kidney disease and heart failure. who enrolled in a treadmill exercise program of 8
In hypertensive adults in NHANES,27 ACE inhib- to 12 weeks lowered their daytime systolic ambula-
itors and ARBs had a more pronounced antihyper- tory blood pressure by 5.9 mm Hg (± 11.6 mm Hg;
tensive effect in women with obesity than in women P = .03).30 In another study, those who exercised for 60
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RESISTANT HYPERTENSION

minutes in a heated pool 3 times per week for 2 weeks blood pressure elevation with calcineurin inhib-
experienced a reduction of 12 mm Hg in 24-hour itors is typically treated with calcium channel
ambulatory systolic blood pressure and a reduction of blockers
9 mm Hg in diastolic blood pressure.31 • Tyrosine kinase inhibitors
Patients should engage in at least 150 minutes per • Dietary supplements, including ginseng and licorice.
week of moderate-intensity aerobic exercise or 75 minutes The degree of blood pressure effect from these medi-
per week of vigorous aerobic activity.2 Both isometric and cations may vary widely from person to person.
dynamic-resistance exercise have been shown to lower
blood pressure, presenting other options for patients with ■ EVALUATE FOR SECONDARY HYPERTENSION
limited mobility who cannot do aerobic exercise.1
Patients with resistant hypertension should be eval-
Alcohol consumption uated for secondary hypertension, since recognition
Regular alcohol consumption has been shown to and directed therapy may improve blood pressure
increase blood pressure by 1 mm Hg for every 10 g of control. In this section, we discuss common causes of
alcohol consumed (approximately 1 standard drink), an secondary hypertension, the clinical context in which
effect that is reversible within a few weeks of cessation.32 they should be suspected, and the basic screening for
each.
Smoking, chewing, vaping
Nicotine, most commonly contained in cigarettes, Kidney parenchymal disease
vaping fluid, and smokeless tobacco, causes an acute Hypertension is both a cause and a consequence of
rise in blood pressure.33 Cessation should be recom- chronic kidney disease and is common in this patient
mended to all patients in general, and especially to population.37 Of 3,612 patients participating in the
those with resistant hypertension to ameliorate their Chronic Renal Insufficiency Cohort study,38 85.7%
already increased risk of cardiovascular events. had a diagnosis of hypertension at their baseline visit.
Fewer than half (46.1%) had their blood pressure
lower than 130/80 mm Hg.38
Nonsteroidal anti-inflammatory drugs Proposed mechanisms of hypertension in kidney
can raise blood pressure by 2 to 5 mm Hg disease include an upregulated renin-angiotensin-
aldosterone system, increased salt and fluid retention,
at any dose high enough to relieve pain endothelial dysfunction, and increased sympathetic
nervous system activity.39
■ IS THE PATIENT TAKING MEDICATIONS Kidney disease should be assessed and considered as
THAT RAISE BLOOD PRESSURE? a risk factor for resistant hypertension in patients with
Medications that can raise blood pressure include the an elevated serum creatinine or abnormal urinalysis.
following2: Primary aldosteronism
• Nonsteroidal anti-inflammatory drugs, including Primary aldosteronism (ie, hyperaldosteronism) is due
cyclo-oxygenase 2 inhibitors. These drugs are to autonomous hypersecretion of aldosterone. Excess
ubiquitous and can raise blood pressure at any dose circulating aldosterone leads to salt and water reten-
high enough to relieve pain, by 2 to 5 mm Hg34,35; tion and renal potassium wasting, which results in
importantly, low-dose aspirin is not associated hypertension and cardiovascular disease.40
with blood pressure elevation36 Primary aldosteronism is more common than pre-
• Glucocorticoids viously thought and often goes undiagnosed, with a
• Serotonin-norepinephrine reuptake inhibitors prevalence ranging from 8% to 30% in various hyper-
• Estrogen-containing contraceptives and other tensive populations.41 Hypokalemia as a result of renal
estrogen-containing medications; the blood pres- potassium wasting is present in only 9% to 37% of
sure effects of these medications are typically patients who have primary aldosteronism, so this dis-
reversible when the medication is stopped ease can be underrecognized.42
• Sympathomimetics (pseudoephedrine, ephedrine, Measuring the plasma aldosterone-to-renin ratio
cocaine, amphetamine) is the test most often used to screen for primary aldo-
• Vascular endothelial growth factor inhibitors steronism. However, this test has the potential for
• Erythropoietin-stimulating agents false-positive and false-negative results, depending on
• Calcineurin inhibitors (cyclosporine, tacrolimus); whether patients are taking medications that interfere
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 YAHR AND COLLEAGUES

with the renin-angiotensin-aldosterone system, the to reduce the risk of other cardiovascular complica-
cutoff values used, the time of testing, and the body tions, a meta-analysis found only a modest reduction
positioning at the time of testing (morning preferred, of 2.46 mm Hg in systolic blood pressure.47 Obesity
after being seated for 15 minutes). The Endocrine and obstructive sleep apnea are both risk factors for
Society guidelines43 recommend initial testing with resistant hypertension, but a study that looked at the
the aldosterone-renin ratio followed by a confirma- effect of CPAP therapy on blood pressure in patients
tory test (intravenous or oral salt-loading test) for with obesity vs those without obesity found no signif-
patients with hypertension who are at risk of primary icant difference between the groups.48
aldosteronism.43 Patients at risk include those with Given the high prevalence of obstructive sleep
resistant hypertension on optimal therapy, those with apnea in those with resistant hypertension, screening
hypertension with spontaneous or diuretic-induced for it should be common in this population. Screen-
hypokalemia, and those with hypertension with adre- ing tools such as the STOP-BANG score can help
nal incidentaloma, as well as hypertensive first-degree risk-stratify patients who have suggestive symptoms
relatives of patients with primary aldosteronism. and who should be tested with polysomnography, the
An aldosterone-renin ratio of 20 or higher gold standard for diagnosis.49 (STOP-BANG consists
should warrant further investigation if the plasma of 8 factors, which spell the acronym: snoring, tired
aldosterone concentration is 15 ng/dL or higher.40 or sleepy during the day, observed stopping breathing
Patients with very low renin levels, spontaneous while sleeping, high blood pressure, body mass index
hypokalemia, and a plasma aldosterone concen- higher than 35 kg/m2, age older than 50, neck circum-
tration higher than 20 ng/dL likely do not require ference ≥ 17 inches if a man or ≥ 16 inches if a woman,
confirmatory testing and should move forward with and male gender. If 3 or more factors are present, the
adrenal imaging. patient has a high risk of obstructive sleep apnea.)49
Primary aldosteronism is treated with surgery
if a unilateral aldosterone-secreting adenoma is Renovascular hypertension
found, or is treated with mineralocorticoid receptor Renovascular hypertension is a syndrome of elevated
antagonists such as spironolactone or eplerenone in blood pressure due to diminished renal arterial blood
bilateral adrenal disease and in patients who are not flow resulting in kidney ischemia.2 It is most com-
candidates for surgery. monly caused by atherosclerosis of the renal arteries,
A full discussion of primary aldosteronism is but other pathologic processes include fibromuscu-
beyond the scope of this article, but screening and lar dysplasia, renal artery infarct or dissection, and
diagnosis according to current guidelines may detect vasculitis.
only a fraction of patients with primary aldostero- The diagnosis of renal artery stenosis includes
nism, and a revamping of current practice guidelines imaging with duplex ultrasonography, computed
is needed. tomography angiography, or magnetic resonance
angiography. At least 70% of the renal artery must
Obstructive sleep apnea be stenosed before the lesion can be considered to be
Obstructive sleep apnea is very common in patients causing the hypertension.
with resistant hypertension.44 Proposed mechanisms Atherosclerotic renovascular disease is considered
by which it could cause or worsen hypertension a coronary artery disease equivalent, and its treatment
include increased upper-airway resistance, hypoxia, consists of medical management focused on blood
and hypercapnia.45 These cause endothelial reactiv- pressure, lipid and glucose control, and antiplatelet
ity, inflammation, oxidative stress, and increased sym- therapy. Percutaneous revascularization should gen-
pathetic and renin-angiotensin-aldosterone system erally be considered in patients with the following
activity, which ultimately lead to increased vascular high-risk features:
tone and hypertension.2,45 • Recurrent heart failure or unexplained flash pul-
Treating obstructive sleep apnea with continuous monary edema
positive airway pressure (CPAP) in patients with resis- • Resistant hypertension with failure of optimal
tant hypertension has been shown to decrease 24-hour medical management
ambulatory blood pressure, and the more hours per • Unexplained rapid decline in glomerular filtration rate
night that patients actually use it, the greater the • Bilateral renal artery stenosis or a single function-
effect on blood pressure.46 However, although treating ing kidney with stenosis associated with any of the
obstructive sleep apnea with CPAP is recommended above.50
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RESISTANT HYPERTENSION

Other endocrinopathies Patients with resistant hypertension should be

Catecholamine-secreting tumors such as pheo- screened for end-organ damage—eg, with serum
chromocytomas and paragangliomas are rare causes of creatinine and urinalysis to look for kidney disease,
hypertension, accounting for 0.2% to 0.6% of cases, electrocardiography or echocardiography to assess for
but are associated with significant mortality risk.51 left ventricular hypertrophy, and an ophthalmologic
Symptoms that should prompt screening include par- examination to look for hypertensive retinopathy.
oxysmal headaches, diaphoresis, and tachycardia.52
The 2014 Endocrine Society guidelines51 recom- Pharmacologic therapy
mend screening by measuring either plasma free meta- Prescribing antihypertensive therapy begins with
nephrines or 24-hour urine fractionated metanephrines. identifying comorbidities that require first-line
Patients who have plasma metanephrines measured agents that have a compelling indication, such as
should lie supine for at least 30 minutes before sampling. beta-blockers for heart failure, history of myocardial
Normetanephrine and metanephrine levels 3 or more infarction, or aortic dissection, or drugs that block the
times higher than the upper limit of normal are highly renin-angiotensin-aldosterone system for proteinuria.
suggestive of a catecholamine-producing tumor. The initial pharmacologic approach to resistant
Medications that can lead to elevated levels of hypertension consists of 3 medications, each mechanis-
metanephrines and catecholamines include tricyclic tically different, at maximally tolerated doses, as follows:
antidepressants, amphetamines, monoamine oxidase • An ACE inhibitor or ARB (ARBs may better tol-
inhibitors, and levodopa, and withdrawal from cloni- erated than ACE inhibitors, as they do not carry
dine can have the same effect. the same risk of angioedema or cough, and some
Cushing disease or syndrome (hypercortisolism experts recommend them as initial therapy over
from glucocorticoid excess) is a relatively uncommon ACE inhibitors54)
cause of resistant hypertension. Cushing syndrome is • A long-acting dihydropyridine calcium channel blocker
a constellation of symptoms that classically include • A diuretic.
glucose intolerance, acne, osteoporosis, obesity, men- In patients with preserved glomerular filtration
strual changes, hirsutism, muscle wasting, and moon rate, the preferred first-line diuretic is either chlorthal-
facies. Interestingly, in one study, 26.5% of patients idone or indapamide because of their longer half-life
with resistant hypertension but no overt signs and and more potent antihypertensive effect compared
symptoms of Cushing syndrome had biochemical evi- with hydrochlorothiazide.55,56 Loop diuretics are pre-
dence of hypercortisolism,53 suggesting that clinicians ferred in patients with an estimated glomerular filtra-
should consider testing for it in patients without the tion rate less than 30 mL/min/1.73 m2. Torsemide can
classic syndrome. Patients should be screened by mea- be used once a day, but shorter-acting loop diuretics
suring the 24-hour urine cortisol level or late-night such as furosemide or bumetanide must be dosed at
salivary cortisol level, or by a low-dose dexametha- least twice a day.1 A recent randomized controlled
sone suppression test. trial showed that chlorthalidone was effective in
Less common endocrine disorders that can con- those with an estimated glomerular filtration rate of
tribute to resistant hypertension include disorders of 15 to 30 mL/min/1.73 m2, thus representing another
the thyroid and parathyroid glands. Thyroid-stim- available agent in this population.57
ulating hormone should be checked in those with If blood pressure is still not controlled on maximally
difficult-to-control hypertension. Testing for primary tolerated therapy with these 3 agents, a mineralocorti-
hyperparathyroidism should be considered in any coid receptor antagonist (spironolactone or eplerenone)
patient presenting with hypercalcemia. should be the fourth-line agent. The PATHWAY-2
trial57 demonstrated that spironolactone was superior
■ MANAGEMENT OF RESISTANT HYPERTENSION in reducing blood pressure compared with bisoprolol (a
beta-blocker), doxazosin (an alpha-blocker), or placebo
All patients diagnosed with resistant hypertension as add-on therapy in patients with resistant hypertension
should be screened for causes of secondary hyperten- on 3 blood pressure medications.57
sion based on history, physical findings, and individ- Side effects of spironolactone include hyperkale-
ual risk factors. A multifactorial approach to treat mia and gynecomastia, and the drug should be used
resistant hypertension includes a combination of life- with caution in chronic kidney disease. If gyneco-
style modification, pharmacotherapy, and addressing mastia becomes intolerable, spironolactone can be
underlying contributing diseases. switched to eplerenone, a selective aldosterone recep-
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 YAHR AND COLLEAGUES

tor antagonist that has minimal interaction with sex Patients should be referred to a hypertension spe-
hormone steroid receptors. However, spironolactone cialist if blood pressure remains uncontrolled despite
is preferred since it has been extensively studied, costs the above therapies.
less, and requires only daily dosing because of its lon-
ger half-life compared with eplerenone.58 Devices and next steps
The addition of other agents should be based Experimental devices and other therapies are cur-
on individual factors. Vasodilating beta-blockers rently being explored in patients with resistant hyper-
(labetalol, carvedilol, nebivolol, bisoprolol) may be tension. Renal denervation to blunt sympathetic
the preferred fifth-line agent. Other choices include tone showed no benefit in the Renal Denervation in
clonidine, a centrally acting alpha-2 agonist. Cloni- Patients With Uncontrolled Hypertension (SYM-
dine can be given as a transdermal patch to improve PLICITY HTN-3) study.61 The Study of the ReCor
adherence, minimize frequent oral dosing, and lower Medical Paradise System in Clinical Hypertension
the risk of rebound hypertension. (RADIANCE-HTN TRIO),62 utilizing a newer
catheter design and a stricter medication protocol,
According to the AHA guidelines, if blood pres-
demonstrated a decrease of 5.8 mm Hg compared
sure is still not at goal, hydralazine may be initiated
with controls, a modest benefit.62
at a starting dose of 25 mg 3 times a day, with the
Other experimental therapies aimed at sympa-
addition of a nitrate in the presence of heart failure
thetic tone modulation include carotid baroreceptor
with reduced ejection fraction.2 Finally, minoxidil
activation therapy and carotid baroreceptor ampli-
may be used if hydralazine is not tolerated. Hydrala-
fication therapy. None of these device therapies are
zine and minoxidil are associated with fluid retention
currently FDA-approved, and more studies are needed
and reflex tachycardia.
to determine their long-term efficacy and safety. ■
Recent studies have shown that aldosterone
synthase inhibitors and dual endothelin antagonists ■ DISCLOSURES
may be effective in resistant hypertension. While
Dr. Calle has disclosed being an advisor or review panel participant for
neither are approved at this time by the US Food Precision Biosciences, and teaching and speaking for Travere Thera-
and Drug Administration (FDA) for this indication, peutics. Dr. Taliercio has disclosed being an advisor or review panel
participant for Otsuka Pharmaceuticals. The other authors report no
these agents may represent additional treatment relevant financial relationships which, in the context of their contribu-
options upon further study.59,60 tions, could be perceived as a potential conflict of interest.

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