CHAPTER 71
DRUG-RESISTANT
HYPERTENSION
SANDRA J. TALER, MD
The prevalence of resistant hypertension is increasing,
fueled by an aging population and the stepwise lowering
of blood pressure targets. Within our tertiary hyperten-
sion practice, resistant hypertension is now the most
frequent reason for referral. Self-referral is also common
because patients are increasingly aware of the importance
of blood pressure control yet are frustrated by prescrip-
tion of increasing numbers of medications and their fail-
ure to achieve blood pressure goals. Limited laboratory
testing may be normal or may harbor clues to a
secondary cause that has been missed. Patients with resis-
tant hypertension carry a high cardiovascular risk burden
with significant comorbidities and subclinical or even
symptomatic target organ damage. A detailed evaluation
of these patients provides an opportunity to detect and
resolve lifestyle or drug interactions, adjust and simplify
often complex medication regimens, and treat or defini-
tively exclude a reversible cause, thereby attaining blood
pressure goals.
Definitions
Resistant hypertension is defined as failure to control
blood pressure to < 140 mm Hg systolic and 90 mm Hg
diastolic using a rational combination of three or more
antihypertensive agents, including a diuretic.1 Refractory
hypertension is a broad term designating treatment fail-
ure using two or more agents; the terms are sometimes
used interchangeably. With recent trends to lower rates of
diuretic prescription,2 some patients present taking three
or more agents without a diuretic. Although outside the
classic definition, these patients may be considered to
have drug-resistant hypertension as well. Using blood
pressure targets of < 140/90 mm Hg, reported prevalence
rates for resistant hypertension vary from < 1% at a
614
hypertension job site clinic to 11 to 13% in referral clin-
ics. 3,4 The prevalence rates are higher for those with
cardiac or renal compromise as goal blood pressure levels
are lowered to < 130/80 mm Hg in the setting of target
organ damage. Even under expert guidance, these lower
targets are difficult to achieve. Surveys of two nephrology
practices reported control rates of 15% to < 125/75 mm
Hg in a population of 201 patients with proteinuric renal
disease5 and 5% to < 130/85 mm Hg for 107 patients at
initiation of dialysis support. 6 These patients with
evident target organ damage carry a disproportionately
high risk of cardiovascular events.7
Causes
An overview of causes of resistant hypertension is shown
in Figure 71-1. Many of these conditions are addressed in
other chapters and are discussed only briefly here. As the
diagnosis of drug-resistant hypertension may be
confounded by stereotypic blood pressure elevations at
physician visits, termed “office” or “white-coat hyperten-
sion” (see Chapter 62, “White Coat and White Coat
Worse Hypertension”), out-of-office measurements are
essential to the identification of true resistance. 8
Advances in technology now provide convenient afford-
able electronic units for home (see Chapter 68, “The Role
of Self-Measured Home Blood Pressure Measurement”)
or out-of-office measurement. We use multiple
approaches to blood pressure measurement, including
standardized American Heart Association measurements
by trained nurses, shortened versions of ambulatory
blood pressure monitoring (see Chapter 67, “Ambulatory
Blood Pressure Monitoring: Its Use in Clinical Practice
and Implications for Therapy”), and patient home
measurements with physician review.9–11 With increasing

Figure 71-1 Causes of drug-resistant hypertension. Many causes relate to physical or lifestyle factors.
prevalence of obesity in the Western world, the large
adult arm cuff is appropriate for most patients. Accurate
measurement is particularly challenging in the morbidly
obese patient, for whom cuff size may be inadequate
because home blood pressure cuffs are limited to stan-
dard and large sizes. Electronic wrist measurement
devices are becoming more reliable and may be a better
choice in this setting.
Volume expansion is well recognized as a cause of
resistance to antihypertensive therapy yet may not be
evident clinically.12,13 The mechanism of resistance is an
insensitivity to standard diuretic therapy, perhaps medi-
ated by obesity and the sodium-retaining properties of
antihypertensive agents, regardless of renal function.
Plasma volume is normal in untreated essential hyper-
tensive patients but increased in patients with renal
parenchymal disease.14 Measurements in resistant hyper-
tensive patients support a positive correlation between
measured blood volume and systolic and diastolic blood
pressure in patients treated with sympatholytic agents or
vasodilators.13 Intensified diuretic treatment improves
blood pressure control by a reduction in plasma
volume. 12,13,15,16 Clinical assessment of effective
cardiopulmonary volume may be misleading because the
presence of peripheral edema using calcium channel
blocking agents may not accurately reflect total body
sodium. 17 Other markers of volume status, such as
plasma renin activity, can be affected by numerous drugs
and other conditions. Drug resistance may result from
combination antihypertensive therapy, a consequence of
Drug-Resistant Hypertension / 615
the use of multiple agents leading to secondary volume
retention and activation of the sympathetic nervous
system or the renin-angiotensin-aldosterone system.
Increased fluid volume occurs commonly as a compen-
satory response to antihypertensive therapy and may
manifest as fluid retention (weight gain, edema) or a
poor response to increased doses of other antihyperten-
sive agents. Graves and colleagues used measurements of
plasma volume to adjust therapy in nine patients with
resistant hypertension.16 Plasma volume was increased in
eight patients, all of whom responded to aggressive
diuretic therapy and simplification of their regimens. In
one patient with contracted plasma volume, vasodilation
was effective in controlling blood pressure. None of the
patients had clinical evidence of volume overload, and
those with expanded plasma volume were already taking
diuretic agents, either thiazide or loop diuretics at
conventional dosages.
Medication-related causes of drug resistance may
originate with the provider or the patient. Nonadherence
is more likely with increasing the complexity of treat-
ment, number of agents, and dosing frequency.
Medication intolerance or side effects and high costs
contribute to missed or reduced dosages and result in
inadequately treated hypertension or acceleration to
more severe levels. 18 There are no obvious clues to
nonadherence, and its true contribution to resistance is
not known. To evaluate the impact of patient adherence,
Nuesch and colleagues compared blood pressure control
by 12-hour ambulatory blood pressure monitoring to
616 / Advanced Therapy in Hypertension and Vascular Disease
medication use as recorded by electronic medication
containers.19 Adherence to treatment, defined as taking at
least 80% of prescribed doses, was similar in those
controlled on medication (85%) and those with
treatment-resistant hypertension (82%).
Despite the availability of several new classes of antihy-
pertensive agents over the past two decades, suboptimal
selection and inappropriate drug combination remain
among the most common causes of treatment failures. In
a series of 91 patients with resistant hypertension referred
to a tertiary care center, 43% were felt to be resistant
owing to suboptimal therapy, another 10% owing to
noncompliance, and 14% from adverse effects.20 The
results from randomized clinical trials indicate that 19 to
47% of enrolled hypertensive subjects require two or
more antihypertensive agents to achieve treatment
goals. 21–24 For patients with manifest target organ
damage, diabetes mellitus, or renal disease for which
treatment goals are lower (< 130/80 mm Hg), 78 to 93%
require two or more medications.25,26 Current guidelines
advise initiation of treatment with combination agents if
starting pressures are 20 mm Hg systolic or 10 mm Hg
diastolic above targets to improve early response and
compliance. 27 Whereas the synergy of diuretics with
angiotensin-converting enzyme inhibitors or angiotensin
receptor blockers is well established, the effects of other
combinations are less clear. Fixed-dose combination ther-
apy agents are limited to those brought forth from the
pharmaceutical industry and may provide convenience or
marketing advantages rather than greater efficacy. For
treatment with more than two agents, there are few data
evaluating the added efficacy of a third and fourth agent
or the risks of drug interactions or side effects.
Several reports implicate physician inattention as a
cause of inadequate blood pressure treatment. Hymen
and Pavlik analyzed data from the National Health and
Nutrition Examination Survey to determine patient
characteristics and health care practices that contribute
to poor blood pressure control.28 Among treated hyper-
tensive patients, control rates fell with increasing
patient age. The predominant elevation was in systolic
pressure, and the extent of elevation above target blood
pressure was mild. Blood pressure was not adequately
controlled even though patients had access to their
health care providers. Berlowitz and colleagues exam-
ined practice patterns w ithin the Veterans
Administration system to elucidate clinical factors that
led to intensified therapy.29 Although blood pressure
was poorly controlled in many, there was a clear link
between more intensive treatment and improved
control. Oliveria and colleagues queried physicians 10
to 90 days after a patient visit regarding reasons that
they changed or did not change treatment.30 The most
frequently cited reason for no change was satisfaction
with blood pressure control, even though blood pres-
sure remained above national targets.
Resistant hypertension commonly results from the
effects of concurrent drug use or drug interactions that
interfere with antihypertensive treatment efficacy (see
Chapter 55, “Erythropoietin-Induced Hypertension”;
Chapter 56, “Immunosuppression”; and Chapter 57,
“Cyclooxygenase inhibition and blood pressure regula-
tion”). Although numerous drugs cause potential inter-
ference, the most common and most significant today is
the nearly universal use of nonsteroidal anti-inflamma-
tory agents and cyclooxygenase 2 inhibitors, causing
sodium retention and reduced drug efficacy of many
antihypertensive agents. A variety of vasoconstrictive
sympathomimetic agents may cause hypertension or
exacerbate control. Among these are cold remedies
containing agents such as phenylephrine, pseu-
doephedrine, and, until recently, phenylpropanolamine.
Numerous herbal preparations containing ephedra, ma
huang, St. John’s wort, or ginseng have been associated
with worsened hypertension. 31 Confectioners’ black
licorice and chewing tobacco contain glycyrrhizic acid,
causing a clinical picture suggestive of primary aldostero-
nism. Other prescription medications may also aggravate
hypertension, including the immunosuppressive agents
cyclosporine and tacrolimus and er ythropoietin.
Medications used for treatment of mood disorders or
depression (eg, methylphenidate, modafinil, venlafaxine)
can produce labile and sometimes severe rises in blood
pressure. Sibutramine, an anorexiant/stimulant used for
weight reduction, may cause or exacerbate hypertension
by inhibiting catecholamine reuptake.
Equally important to drug interactions are lifestyle
factors, including obesity, high sodium intake, and exces-
sive alcohol use (see Chapter 11, “Salt Intake Reduction,”
and Chapter 13, “Alcohol and Hypertension”), that may
cause hypertension or contribute to drug resistance. In the
milieu of a high sodium intake so common in our society,
most patients show no outward signs of volume excess.
Recent trends to use of very low-dose diuretic therapy or
avoidance of diuretics 2 may trigger drug resistance.
Ethanol abuse may be easily overlooked yet contributes to
drug resistance and poor adherence to treatment.
Secondary Hypertension
Secondary hypertension is the presence of a specific
condition known to cause hypertension. Major
secondar y causes of hypertension are shown in
Figure 71-2. This condition may be the primary cause of
hypertension in an individual or a contributing factor in
a patient who also has essential hypertension. Secondary

hypertension may cause drug resistance related to
increased severity and underlying hormonal abnormali-
ties. Whereas the Yakovlevitch and Black series reported a
prevalence of 11%,20 our own experience suggests that it
may be more common, as noted in 31% of a group of
104 patients enrolled in a resistant hypertension treat-
ment trial. 32 In some situations, correction of the
secondary cause, even if feasible, does not resolve the
hypertension. Although 13% in our series received treat-
ment directed specifically at the secondary cause, they
remained resistant to therapy. This underscores the chal-
lenge of distinguishing between the presence of an exac-
erbating condition and its contribution to resistance. The
rates of secondary hypertension reported in other series
range from 6 to 18%. 33,34 The prevalence rates vary
widely depending on whether patients are screened prior
to the diagnosis of resistant hypertension and the extent
of screening or exclusions.
Even with secondary hypertension, some individuals
can be treated to goal blood pressure levels using medical
therapy. Decisions regarding the extent of evaluation
appropriate must consider the patient’s age, long-term
prognosis, and adequacy of medical therapy and then
balance the risks of leaving the condition undetected
against the risks of treatment. If intervention risks are
prohibitive, one should consider forgoing complex diag-
nostic procedures. Patient response to medical treatment
and tolerance of that treatment must be reviewed. If
medical therapy fails, one may need to then go back and
address the secondary cause.
Figure 71-2 Causes of secondary hypertension.
Drug-Resistant Hypertension / 617
Recent trends in hypertension management empha-
size lifestyle changes and early initiation of drug treat-
ment with limited laboratory investigation. Thus, many
hypertensive patients receive treatment without testing to
exclude secondary causes. The most common indication
for secondary evaluation is failure to achieve blood pres-
sure targets after prescription of escalating numbers and
doses of medication. Secondary hypertension is more
likely when the clinical picture departs from expected
patterns with atypical features in the patient’s history,
clues on physical examination, or unexpected laboratory
findings (Table 71-1). The overriding goal of testing is to
evaluate and correct potential causes and thereby
improve blood pressure response to the prescribed anti-
hypertensive medications. It is appropriate to consider
curable forms of hypertension, although they are rare.
The diagnosis of hypertension in a young person merits
more aggressive evaluation because the long-term
economic and medical costs of drug treatment over a
lifetime are substantial, even if the blood pressure is well
controlled. In this setting, early diagnosis may provide an
opportunity for cure that will be lost later if hypertension
persists over a longer time. In older individuals, the fail-
ure to achieve blood pressure targets or a progressive
decline in renal function prompts reconsideration of a
secondary cause. Renal parenchymal disease is the most
common secondary cause, but urinary outlet obstruction
should be considered. Renovascular disease occurs in
young women as fibromuscular dysplasia and in older
individuals owing to atherosclerotic renal artery stenosis.
618 / Advanced Therapy in Hypertension and Vascular Disease
Table 71-1. Atypical Features Suggesting Secondary Hypertension
Historical clues
Early age at onset
Severe or accelerated course18,57,58
Absent family history of hypertension
Resistant hypertension
Specific drug intolerances
Marked hypokalemia on diuretics
Worsening hypertension after -blockade
Acute renal failure on ACEI, ARB
Symptoms
Spells, lability, orthostatism
Prostatism
Snoring, daytime hypersomnolence
Flash pulmonary edema
Physical examination clues
Café au lait spots, neurofibromas
Cervical fat pad, moon facies, pigmented striae
Thigh BP lower than brachial BP, continuous murmur over back
Goiter or thyroid nodule
Large neck, narrow pharynx
Abdominal systolic-diastolic bruit, multiple arterial bruits
Large palpable kidneys
Laboratory clues
Hyperkalemia
Hypokalemia
Elevated serum creatinine
Abnormal urinalysis
Loss of nocturnal BP fall
Disproportionate target organ damage
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP = blood pressure.
Endocrine causes include primary aldosteronism,
pheochromocytoma, and cortisol or thyroid abnormali-
ties. Obstructive sleep apnea is an increasing problem
with the current obesity epidemic and may mediate a
relative aldosterone excess state.35,36
An extensive discussion of the workup of secondary
hypertension is beyond the scope of this chapter, and the
reader is referred to other chapters and in-depth
reviews.37–39 Once the diagnosis of drug-resistant hyper-
tension has been made and potential lifestyle factors and
drug interactions have been addressed, it is time to
consider additional testing for potentially treatable
secondary causes. For the patient with resistant hyperten-
sion, one must begin with a general consideration of
multiple secondary causes and then focus on contribut-
ing mechanisms based on preliminary test results.
Beyond the basic laboratory tests advised by the Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood
Pressure (JNC 7), preliminary testing should include a
noninvasive imaging study of the kidneys and renal
arteries and hormonal screening for excess aldosterone or
catecholamine states. It is important to distinguish renal
Primary or secondary hyperaldosteronism, corticosteroid excess
Pheochromocytoma
Renovascular hypertension
Pheochromocytoma
Urinary obstruction
Obstructive sleep apnea
Renovascular hypertension
Pheochromocytoma
Cushing’s disease
Aortic coarctation
Thyroid disease
Obstructive sleep apnea
Renovascular hypertension59
Polycystic kidney disease
Renal parenchymal disease, urinary obstruction
Renovascular hypertension, primary or secondary hyperaldosteronism
Renal parenchymal disease, urinary obstruction, renovascular hypertension
Renal parenchymal disease
parenchymal disease from renovascular hypertension.
Parenchymal renal disease is characterized by an elevated
serum creatinine level and, in some settings, an active
urinary sediment. Renal biopsy may be necessary for
definitive diagnosis. Renal outflow tract obstruction
owing to prostatic obstruction, mass lesion, or complica-
tions of prior surgery should be excluded before moving
to invasive vascular testing. Normal renal imaging and a
bland urinary sediment suggest renal vascular disease
and, coupled with drug-resistant hypertension, merit
further vascular imaging. Significant renal vascular
disease causing resistant hypertension or progressive
renal dysfunction may respond well to renal revascular-
ization, and for selected individuals, percutaneous or
surgical intervention may salvage critical renal function.
Clinical features should guide the investigation of
hormonal secondary causes. Hyperaldosteronism is
increasingly recognized as a correctable cause of resistant
hypertension; thus, screening should be considered early
in the evaluation (see Chapter 38, “Elevated Aldosterone-
Renin Ratio”). The obese patient with resistant hyperten-
sion may have a relative aldosterone excess but fall short
of the classic criteria for primary aldosteronism.
 Drug-Resistant Hypertension / 619

Chemokines in visceral fat may stimulate the renin-
angiotensin-aldosterone system, particularly in patients
with concurrent sympathetic activation from untreated
sleep apnea.35
Less common secondary causes may present with
subtle findings, and directed testing may be appropriate.
The pursuit of secondary causes is intended to ensure
treatment of all potential contributing mechanisms so
that blood pressure control is achieved. At each step in the
pathway, the clinician must decide whether the condition
has been sufficiently excluded in the individual patient or
whether more definitive testing is indicated. Such deci-
sions should consider the patient’s age, long-term progno-
sis, risks of leaving the condition undetected, risks of
intervention, and adequacy of medical therapy.
Treatment Approaches
Nonadherence with prescribed medications can at times
be addressed by simplifying the regimen or changing to
agents better tolerated by the individual patient. Some
individuals label themselves intolerant to agents that
were ineffective in past trials, as monotherapy or in other
combinations. Use of different combinations or different
doses may be effective and well tolerated. In examining
the preexisting drug regimen, the use of agents with over-
lapping mechanisms of action, or at inadequate doses,
should be considered. Blood pressure lability or loss of
blood pressure control may occur with the use of short-
acting agents or rapid drug metabolism.
Early treatment trials used standardized multidrug
regimens, with each agent added in stepwise fashion
starting with a diuretic or -adrenergic blocker and then
adding peripheral vasodilator agents. These trials were
not randomized because the more potent agents were
reserved for those most refractory.4,40 Intensified treat-
ment was limited by an increase in side effects. More
recently, Yakovlevitch and Black controlled blood pres-
sure in 34 patients and improved blood pressure in
another 8 of 46 patients with resistant hypertension
attributed to a suboptimal treatment regimen.20 For half
of these patients, diuretic therapy was started or intensi-
fied. In another 17 patients, the addition of a newer agent
or the reduction in sympatholytic medications led to
improved blood pressure. There were no specific guide-
lines or clinical features used to guide treatment changes.
Studies by Nishizaka and colleagues and others reported
incremental blood pressure reduction from the addition
of low-dose spironolactone to multiagent regimens in
subjects with and without primary aldosteronism.41,42
The extent of blood pressure reduction was comparable
in those with and without demonstrated aldosterone
excess.
Beyond traditional triple-agent therapy, there are no
randomized studies to guide the selection of complex
antihypertensive treatment. One can add a fourth agent,
use higher than recommended doses of those agents
already prescribed, or substitute another agent from the
same drug class to see if there is a better individual
response. New medications should be introduced indi-
vidually to simplify the interpretation of drug reactions
or side effects should they occur. Some centers advocate
algorithms for drug selection. Examples are listed in
Table 71-2. The Birmingham Hypertension Square is
designed to optimize the choice of add-in drugs in the
management of resistant hypertension.43 One can choose
any of four agent classes on the corners of a square, based
on the clinical characteristics of the patient or
compelling indications, as specified in JNC 7. If a single
agent is not effective, one would select a second agent
using one of the drug classes adjacent on the square to
the initial selection while avoiding the selection at the
corner opposite to that initial choice. Variations to this
schematic have also been published.44 The evidence for

Table 71-2 Treatment Approaches to Resistant Hypertension

Strategy Method
System change approach Nurse-physician team with nurse follow-up45
Nurse-based follow-up and drug titration46
Rapid titration followed by home measurement reports to nurse11
Add-on treatment Not randomized, usually single add-on agent
Fourth agent
Higher than recommended doses
Substitute another agent from same drug class
Treatment algorithms Birmingham Hypertension Square43
Round 1, Round 244
Treatment using serial measurements Laragh method of sodium-volume and renin vasoconstrictor drugs47
Hemodynamic measurements by thoracic bioimpedance32
Attention to volume Plasma volume measurements16
Volume assessment by thoracic bioimpedance32
Empiric use of combination diuretic treatment
620 / Advanced Therapy in Hypertension and Vascular Disease
this approach is based on a few small trials using limited
agents and small patient numbers extrapolated to
produce generalizations about entire drug classes and the
resistant hypertension population. Within this approach,
the selection of a third drug remains speculative. Other
approaches to treatment focus on system changes for
intervention45,46 and follow-up.11 Stroebel and colleagues
reported the use of a team approach with a nurse safety
net using nurse measurements and an algorithm for
repeat measurements to maintain the focus on blood
pressure until control was achieved. 45 Control rates
improved from 33 to 50% during the intervention period
and remained at 56% 1 year later. Corresponding rates for
the control group were 25% at entry, 31% at the end of
the intervention, and 24% 1 year later. Denver and
colleagues reported threefold greater hypertension control
rates using a nurse-led hypertension clinic compared with
conventional primary care.46 Patients were seen monthly
for blood pressure measurement, review of medication
adherence and recommendations for lifestyle interven-
tions, and initiation of physician-supervised medication
adjustments. Canzanello and colleagues demonstrated the
long-term efficacy of rapid physician-directed medication
titration over days followed by interval home blood pres-
sure measurements and medication adjustments over 1
year to achieve and maintain extended control. 11
Although these approaches may be effective, most of the
patients in these treatment trials did not have resistant
hypertension but less severe forms.
Beyond these system change approaches, some experts
use spot measurements to adjust complex drug therapy.
The Laragh method classifies antihypertensive agents
according to their effects on sodium volume and renin
vasoconstrictor determinants of blood pressure. Using a
standardized measurement of plasma renin, medications
are selected to correct the primary pathologic mecha-
nism behind the blood pressure elevation, either a high
sodium and volume state or a renin-angiotensin–medi-
ated vasoconstricted state.47 Serial measurements are
used to guide treatment decisions and titrate or alter
treatment for patients already taking medications who
remain hypertensive (Laragh Protocol II). We use nonin-
vasive hemodynamic measurements obtained by thoracic
bioimpedance to adjust and change complex antihyper-
tensive treatment. The premise of this approach is to
control the compensatory responses to initial treatment
by use of antihypertensive agents with different hemody-
namic actions. Although it is recognized that effective
blood pressure control requires a reduction in vascular
resistance, the effects of specific drugs can be heteroge-
neous and can lead to both volume retention and reflex
changes that offset the desired result.13,48,49 Although the
use of hemodynamic measurements to characterize blood
pressure disorders is not new,50–52 previous efforts were
limited by a lack of noninvasive reproducible measure-
ments. Recent developments have improved the consis-
tency and reliability of systemic hemodynamic
measurements using thoracic bioimpedance in normal
and disease states.53–56 This technique detects changes in
thoracic fluid volume during electrical systole using skin
electrodes and a low-voltage current to derive stroke
volume. Coupled with heart rate and blood pressure
measurements, thoracic impedance offers real-time
measurement of cardiac output and systemic vascular
resistance (Figure 71-3). Absolute impedance measure-
ments and changes in impedance with posture change
from a supine to a standing position serve as markers of
cardiopulmonary volume, based on data from normal
subjects studied on controlled sodium intakes. Application
of this method in a randomized clinical trial demonstrated
improved control rates and lower blood pressure levels in
resistant hypertensive patients using serial hemodynamic
measurements compared with standard drug adjustment
made by hypertension experts. Improved blood pressure
control correlated with a greater reduction in systemic
vascular resistance in those treated according to hemody-
namic values. Although nearly all subjects were taking a
diuretic at entry (91%), more intensive diuretic therapy
was prescribed in the hemodynamic treatment group than
in the specialist care group. Our results indicate that ther-
apy based on hemodynamic measurements with an
emphasis on targeted control of volume using diuretic
therapy achieved blood pressure control superior to that
attained by empiric selection of drugs.
When to Refer Patients for More
Specialized Consultation
Decisions on referral depend largely on the comfort and
experience of the treating practitioner. The discussion in
this chapter is directed to the level of the internist or
subspecialist physician with expertise in the selection and
use of multiple agents for the treatment of hypertension.
Decisions regarding the extent of secondary evaluation
require consideration of the likelihood of diagnosis and
the patient’s overall health status and prognosis and
balancing the risks of intervention against the risks of
missing a diagnosis. Referral is indicated when these risks
appear to be prohibitive, there are questions regarding
selection of optimal studies or extent of intervention, and
blood pressure remains uncontrolled. Referral patterns
vary with regional expertise. Resources include nephrolo-
gists (renal parenchymal disease, renovascular hyperten-
sion, volume overload), pharmacists and pharma-
cologists (drug interactions, regimen simplification,
 Drug-Resistant Hypertension / 621

Figure 71-3 Graphic depiction of hemodynamic measurements obtained on a patient with resistant hypertension using thoracic bioimpedance. The
central box in the left-hand figure depicts normal values. Study 1 displays measurements taken prior to drug intervention and study 2 several weeks
after. Impedance changes with posture, shown on the right, are displayed relative to values from normal subjects on standardized sodium intakes.
622 / Advanced Therapy in Hypertension and Vascular Disease
adherence), and endocrinologists (endocrine secondary
causes, referral and interpretation of adrenal imaging and
adrenal vein sampling).
Conclusions
The availability of multiple effective antihypertensive
medications in recent years offers greater choice in anti-
hypertensive therapy than ever before. Yet hypertension
resistant to treatment with three or more agents remains
a challenge, compounded by the establishment of lower
blood pressure targets. Although suboptimal treatment is
the most common cause, other causes include secondary
hypertension, lifestyle practices, and drug interactions.
Careful evaluation provides the opportunity to treat or
definitively exclude a reversible cause, adjust and simplify
complex medication regimens, and educate the patient
on the effects of lifestyle practices and achieve blood
pressure goals. A variety of treatment strategies are
reviewed, including systems approaches that often
depend on nonphysician providers.
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