REVIEW PAPER

Epidemiology of Resistant Hypertension

Pantelis A. Sarafidis, MD, MSc, PhD

From the Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki,
Thessaloniki, Greece

Resistant hypertension is an entity that has gained a lot of identifiable causes of hypertension were shown to be com-
attention in recent years. The prevalence and prognosis of mon among patients with resistance to antihypertensive
resistant hypertension have not yet been examined by treatment. Importantly, the prevalence of several of these
proper population studies, but data from several sources conditions has been increasing continuously during the past
suggest that this entity is not uncommon and is associated years, suggesting a future increase in the frequency of resis-
with an elevated risk of hypertensive complications. More- tant hypertension. This article will discuss current knowl-
over, several factors and conditions that can interfere with edge and associated future implications relevant to the
blood pressure control such as excess sodium intake, epidemiology of resistant hypertension. J Clin Hypertens
obesity, diabetes, older age, kidney disease, and certain (Greenwich). 2011;13:523–528. 2011 Wiley Periodicals, Inc.

Hypertension represents the most common chronic helped towards the formation of a stable reference
disease in the Western world, with an estimated preva- context for both research activities and clinical
lence in the adult population of more than 25%,1 and discussions in the field in recent years. Resistant hyper-
a major risk factor for cardiovascular disease (CVD), tension was described as failure to achieve goal BP
including coronary artery disease, heart failure and (<140 ⁄ 90 mm Hg in the general hypertensive popula-
stroke, chronic kidney disease (CKD), and death.2–4 tion and <130 ⁄ 80 mm Hg in patients with diabetes or
Thus, suboptimal blood pressure (BP) was previously CKD) when patients adhere to full doses of an
characterized as the primary attributable risk for death appropriate regimen of 3 antihypertensive drugs,
worldwide, accounting for 62% of cerebrovascular including a diuretic.2 According to a relevant position
disease, 49% of ischemic heart disease, and more than statement,6 although this definition may be arbitrary
7 million deaths per year.5 regarding the number of medications required, it has a
Essential hypertension is a disease with complex and clear scope from a clinical standpoint, ie, to identify
incompletely understood etiology. The relative patients who are at high risk of having reversible
contribution of the numerous factors that have been causes of hypertension and ⁄ or patients who, because
implicated in the pathogenesis of hypertension can of persistently high BP levels, may benefit from special
vary substantially among hypertensive individuals and, diagnostic and therapeutic considerations.
thus, efficacy of treatment regimens also varies among Importantly, the above definition does not apply to
subgroups of patients.2 Most importantly, activation patients who have recently been given a diagnosis of
of an increased number of etiologic mechanisms in hypertension and ⁄ or have not yet received appropriate
one individual can result in great difficulties in control- treatment regardless of their BP level.7 In addition,
ling BP even with multiple drugs, ie, in hypertension ‘‘resistant hypertension’’ is not synonymous with
that is resistant to treatment. ‘‘uncontrolled hypertension,’’ which includes all hyper-
This article will discuss the epidemiology of resistant tensive patients without BP control under treatment,
hypertension, including the prevalence and prognostic ie, those receiving an inadequate treatment regimen,
implications of the disease, as well as conditions those with poor adherence, those with undetected
associated with pseudoresistance and truly resistant secondary hypertension, and those with true treatment
hypertension. resistance. Further, a small portion of patients can
have at the same time resistant and controlled hyper-
DEFINITION OF RESISTANT HYPERTENSION tension, ie, patients whose BP is controlled with full
The Seventh Report of the Joint National Committee doses of 4 medications.6,8
on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure (JNC 7) guidelines included a PREVALENCE OF RESISTANT
formal definition of resistant hypertension, which HYPERTENSION
Despite the growing number of clinical studies on
Address for correspondence: Pantelis A. Sarafidis, MD, MSc, PhD, resistant hypertension in the past decade, the preva-
Section of Nephrology and Hypertension, 1st Department of Medicine, lence of this entity has not yet been properly exam-
AHEPA Hospital, Aristotle University of Thessaloniki, St Kiriakidi 1, 54636,
Thessaloniki, Greece
ined. An accurate determination of it would require a
E-mail: psarafidis11@yahoo.gr prospective cohort study in a large hypertensive popu-
Manuscript received November 13, 2010; Accepted: January 22, 2011 lation performing estimations after forced titration to
DOI: 10.1111/j.1751-7176.2011.00445.x full doses of at least 3 antihypertensive medications,

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Epidemiology of Resistant Hypertension | Sarafidis

including a diuretic, as well as exclusion of causes of tion or in patients with diabetes or CKD, inadequate
pseudoresistance. A less informative alternative would control of systolic BP (SBP) is the main culprit
be a cross-sectional study that included an adequate responsible for poor control rates.14,17,18 Similar data
sample of the overall population of unselected hyper- from Europe suggest a much worse situation, with
tensive patients. As of this writing, however, there is a control rates among treated hypertensives ranging
characteristic paucity of studies like the above, and the between 19% and 40% in 5 countries examined in
relevant information is derived from 3 types of studies: large surveys.19 These low rates of control suggest
(1) retrospective cohort studies, (2) data on the control that resistant hypertension is not uncommon, but
of hypertension from population studies, and (3) data accurate estimations cannot be made from such stud-
from the selected populations of major outcome trials. ies since they do not provide information on the
Several retrospective studies have examined the number, type, and dosage of antihypertensive agents
prevalence of resistant hypertension in various settings. used.
Overall, smaller studies suggest a prevalence ranging Another indirect source of data regarding the bur-
from around 5% in general practice, with little selec- den of resistant hypertension is the control rates of
tion of patients, to 50% or higher in nephrology clin- major outcome trials in hypertension, especially of
ics, including patients with CKD.9 Among studies in those with large and diverse cohorts.6,7,20 In such stud-
larger cohorts that examine the epidemiologic charac- ies, medications are provided at no charge, adherence
teristics of resistant hypertension, two included is closely monitored, and titration is dictated by the
patients visiting a tertiary hypertension facility for the protocol. The Antihypertensive and Lipid-Lowering
first time and showed the prevalence to be 11%10 and Treatment to Prevent Heart Attack Trial (ALLHAT)
21%,11 respectively. Perhaps the situation in the gen- enrolled more than 33,000 patients older than
eral hypertensive population is best reflected in a 55 years with hypertension and at least one additional
recent retrospective study that examined records of an cardiovascular risk factor. After 5 years, about 49%
electronic medical database including data from about of participants were controlled on 1 or 2 drugs, and,
100 practice sites and 9700 clinicians (mostly primary at study completion, 27.3% of patients were taking
care specialists). In this study, among 29,474 adult 3 drugs. However, only 68% of patients taking
patients with a diagnosis of hypertension who com- chlorthalidone, 66.3% taking amlodipine, and 61.2%
pleted a yearly follow-up within the system, a diagno- taking lisinopril achieved goal BP.21 In the Losartan
sis of resistant hypertension based on the formal Intervention for Endpoint Reduction in Hypertension
definition could be made in about 9%. Interestingly, (LIFE) study, which included patients with hyperten-
another 6% of the population could not achieve ade- sion and left ventricular hypertrophy (LVH), only
quate control despite taking 3, 4, or more drugs in the 48% of patients taking losartan and 45% taking ate-
absence of a thiazide diuretic.12 Overall, studies of this nolol achieved BP <140 ⁄ 90 mm Hg after a mean fol-
type provide important information, but suffer from low-up of 4.8 years.22 In the International Verapamil-
several limitations, including the retrospective type of Trandolapril Study (INVEST), enrolling more than
the analysis and the fact that relevant data were based 22,000 patients with hypertension and CVD, 65% of
on simple clinical readings and, therefore, no distinc- participants in the calcium antagonist arm and 64% in
tion can be made between pseudoresistance and true the non–calcium antagonist arm achieved the goal for
resistance, as described below. SBP at 24 months of follow-up. These control levels
Data from major population studies on prevalence, were achieved with the use of an average of 3.2
awareness, treatment, and control of hypertension drugs.23 Recent data from the Avoiding Cardiovascu-
can also be used to approximate the prevalence of lar Events Through Combination Therapy in Patients
resistant hypertension. In the United States, the series Living With Systolic Hypertension trial, including
of the National Health and Nutrition Examination hypertensive patients with 1 or 2 additional risk fac-
Surveys (NHANES) suggest that the net and age- tors, suggest that better BP control (around 80% of
adjusted prevalence of hypertension has been con- participants) can be achieved with a strategy of start-
stantly increasing through the past decades, but the ing with fixed-dose combination therapy. However,
proportions of adults with hypertension who are for these control rates to be possible, about 60% of
aware of their disease, receive antihypertensive treat- participants had to receive maximal doses of combina-
ment, and keep their BP under control have also con- tion therapy at 6 months, and 32% of them to be tak-
siderably improved from 1976 to 2000.13,14 Recent ing 3 drugs after 1 year of follow-up.24 All these
data suggest that about 37% of the total hyperten- studies also suggest that resistant hypertension is not
sive population and 58% of patients taking antihy- uncommon. However, such data provide at best only
pertensive medication achieve BP levels <140 ⁄ 90 mm rough approximations of the actual burden of resistant
Hg.14 However, control rates among high-risk indi- hypertension, because, in most cases, a combination of
viduals, ie, patients with diabetes and CKD, are 3 drugs of the classes most commonly prescribed in
much lower, especially with application of the more the clinical setting was not feasible due to the actual
strict BP goal of 130 ⁄ 80 mm Hg for these groups.14– comparisons of each protocol, the populations studied
17
Of note, either in the general hypertensive popula- were relatively older and had additional risk factors,

524 The Journal of Clinical Hypertension Vol 13 | No 7 | July 2011 Official Journal of the American Society of Hypertension, Inc.
 Epidemiology of Resistant Hypertension | Sarafidis

and in some cases patients with difficult to treat hyper- PATIENT CHARACTERISTICS AND
tension were excluded.6 ASSOCIATED CONDITIONS
PROGNOSIS OF RESISTANT HYPERTENSION Factors Related to ‘‘Pseudoresistance’’
Similar to the actual prevalence of resistant hyperten- Pseudoresistance describes the appearance of lack of
sion, the long-term prognosis of individuals with BP control under appropriate treatment in a patient
resistant hypertension compared with hypertensive who does not actually have resistant hypertension.
patients without this syndrome, ie, with hypertension Several factors may contribute to elevated BP readings
controlled with an appropriate regimen of 3 antihy- and produce the perception of resistant hypertension
pertensive drugs, has not been accurately determined. (Table I).6,7,9,20 Previous studies have shown that such
However, relevant lines of evidence again suggest that interfering factors are particularly common in patients
prognosis in treatment-resistant patients who typically referred to hypertension clinics with the diagnosis of
present with a longstanding history of poorly resistant hypertension.10,11 Thus, treating physicians
controlled hypertension is likely to be unfavorable. should carefully evaluate the patient to exclude such
Previous case control studies show that patients with factors before labeling someone as resistant hyperten-
resistant hypertension carry a higher burden of target sive and perform further diagnostic testing and over-
organ damage, such as LVH, carotid intima-media treatment.
thickening, retinal lesions, and microalbuminuria than Improper office BP measurement technique is a fre-
those with satisfactory BP control.25 Most impor- quent cause of pseudoresistance. Several common mis-
tantly, major population studies on hypertension takes (not leaving the patient to sit quietly for
prognosis indicate that the relative risks of myocardial adequate time, single instead of triple readings, use of
infarction, stroke, heart failure, renal failure, and other small cuffs, recent smoking) often result in falsely high
morbidities are directly related to the degree of BP BP readings.6,7,20 The white coat effect (elevation of
elevation.3,4 Further, patients with resistant hyperten- BP during a clinical visit resulting in higher BP read-
sion usually present with a combination of other ings in the office than those in the home or with the
cardiovascular risk factors, such as obesity, diabetes, use of ABPM) is also common, since about 25% of
and CKD, that further elevate the risks of morbidity patients with perceived resistant hypertension turn out
and mortality.26 to have controlled BP when ABPM is used.32 Further,
Of note, recent studies suggest that ambulatory BP the presence of heavily calcified or arteriosclerotic
monitoring (ABPM) may have a special role in arteries that cannot be fully compressed (usually in
assessing cardiovascular risk in resistant hyperten- elderly individuals) can also result in overestimation of
sion. A prospective cohort study including 556 resis- intra-arterial BP.20
tant hypertensive patients showed that elevations in Another frequent finding in patients who appear to
ambulatory SBP and diastolic BP were associated have resistant hypertension is a suboptimal antihyper-
with cardiovascular morbidity and mortality after tensive regimen (eg, inappropriate choices of drugs
adjustment for age, sex, body mass index, diabetes, and combinations for the given patient characteristics,
smoking, physical inactivity, dyslipidemia, previous inadequate doses, inappropriate use of diuretics, no
cardiovascular diseases, serum creatinine, number of intensification of therapy).10,11 Absence of proper
antihypertensive drugs used, and office BP, whereas changes in antihypertensive medication when the
office BP did not have independent prognostic
value.27 Subsequent analyses of the same authors
showed that other parameters derived from ABPM
TABLE I. Factors Related to ‘‘Pseudoresistance’’
recordings, such as non-dipping nighttime BP pattern
and ambulatory arterial stiffness index, were also Improper blood pressure measurement
independently associated with cardiovascular morbid- White coat effect
ity and mortality.28,29 These data suggest that ABPM Heavily calcified or arteriosclerotic arteries
may be useful in resistant hypertension not only for that are difficult to compress (in elderly individuals)
diagnostic (ie, recognizing patients with white coat Related to antihypertensive medication

effect and pseudoresistance) but also for prognostic Inadequate doses

Inappropriate combinations
purposes.
Physician inertia (failure to change or increase
To what extent the risks of morbidity and mortality
dose regimens when not at goal)
related to resistant hypertension are reduced with ade-
Poor patient adherence
quate therapy has not been evaluated.26 However, the
Side effects of medication
benefits of successful treatment in these individuals are Complicated dosing schedules
likely to be substantial, as evidenced by major out- Memory or psychiatric problems
come studies in the field, where the greater the base- Poor relations between doctor and patient
line BP levels and ⁄ or the larger the decrease in BP, the Inadequate patient education
greater the reductions in hypertension-associated target Costs of medication
organ damage.30,31

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Epidemiology of Resistant Hypertension | Sarafidis

patient is not at goal reflects the phenomenon of clini- excretion, increased sympathetic nervous system activ-
cal inertia, which is defined as the conscious decision ity, activation of the renin-angiotensin-aldosterone sys-
of clinicians to not adequately treat a condition despite tem, presence of obstructive sleep apnea, and relative
knowing that it is present in the patient. Relevant reductions in active drug levels.6,20 Importantly, the
studies suggest that this phenomenon is common prevalence of obesity is constantly increasing in devel-
among American physicians who treat patients with oped societies and is the main factor driving the upward
hypertension.33 Poor adherence of the patient to an trends in the incidence of relevant disorders (diabetes,
adequate antihypertensive regimen is another impor- hypertension, and high cholesterol) within the context
tant cause of pseudoresistance.26 Previous studies of the metabolic syndrome.41 Given the associations
report that up to 40% of newly diagnosed hyperten- between obesity and treatment resistance, these trends
sives will discontinue their medications during the first may result in increasing prevalence of resistant hyper-
year and <40% will continue taking their drugs tension. The presence of diabetes also makes hyperten-
during 10 years of follow-up.34,35 Potential causes of sion control difficult, as evident from several
limited adherence include side effects of drugs, compli- population studies, where control rates of hypertension
cated dosing schedules, presence of memory deficits or in diabetic patients were low, especially with the thresh-
psychiatric disorders, poor patient-doctor relation- old of 130 ⁄ 80 mm Hg, despite the efforts to increase
ships, failing to educate the patient on the importance physicians’ awareness on the importance of con-
of achieving BP goals, and high cost of medication, trol.14,42 The increased prevalence of obesity and CKD
which can be very important in countries without pub- among individuals with diabetes are among the major
lic health systems. causes of treatment resistance. The continuous rise in
the prevalence of diabetes41 can also further deteriorate
Factors Contributing to Truly Resistant the problem of resistant hypertension.
Hypertension In addition, older age has been associated with poor
Apart from the aforementioned parameters, a number hypertension control.20 Arterial stiffening with increas-
of lifestyle or biological factors and associated condi- ing age is the cause of a continuous increase in SBP
tions can contribute to failure of achieving BP goals
despite effective treatment, ie, to true resistance
(Table II).
Excess dietary salt leading to volume overload in TABLE II. Factors Contributing to Resistant
susceptible patients is a factor involved in many cases Hypertension
of resistant hypertension. About 90% of patients with
Volume overload
resistant hypertension were shown to have expanded
Excess sodium intake
plasma volume.36 Excessive sodium intake is frequent
Inadequate diuretic therapy
in Western societies and processed foods represent its Volume retention from kidney disease
most common source.6,20 Most hypertensive patients Excess alcohol intake
have inordinately high salt intake, but in patients with Obesity
resistant hypertension, this may be even higher, Diabetes
exceeding 10 g ⁄ d.37 This can contribute to resistant Older age
hypertension both by increasing BP and by blunting Drug-induced
the BP-lowering effect of several classes of antihyper- Nonsteroidal anti-inflammatory drugs (including
tensive agents, effects that are more pronounced in cyclooxygenase-2 inhibitors)
salt-sensitive patients, ie, African American, elderly, Sympathomimetics (decongestants, anorectics)
obese, and those with CKD. Modest consumption of Cocaine, amphetamines, other illicit drugs
alcohol is not generally associated with BP increases, Oral contraceptive hormones
but large amounts (>3–4 drinks daily) are related to Adrenal steroid hormones
increases in BP and the risk of hypertension, while Erythropoietin
reduction of alcohol ingestion was associated with Cyclosporine and tacrolimus
reductions in BP levels.2,38 Earlier data have shown Licorice (included in some chewing tobacco)
that heavy drinkers were much less likely to achieve Over-the-counter dietary and herbal supplements
control of BP compared with hypertensive patients (eg, ginseng, ma huang)

who did not consume large alcohol quantities.39 It has Identifiable causes of hypertension
Renal parenchymal disease
therefore been suggested that heavy alcohol intake
Renovascular disease
may contribute to resistant hypertension.6,7
Primary aldosteronism
Increased body weight is also associated with more
Obstructive sleep apnea
severe hypertension, need for an increased number of Pheochromocytoma
antihypertensive medications, and a decreased likeli- Cushing’s syndrome
hood of achieving BP control.40 Obesity contributes to Thyroid diseases
BP elevation through various mechanisms, such as Aortic coarctation
insulin resistance ⁄ hyperinsulinemia, impaired sodium

526 The Journal of Clinical Hypertension Vol 13 | No 7 | July 2011 Official Journal of the American Society of Hypertension, Inc.
 Epidemiology of Resistant Hypertension | Sarafidis

after the age of 55 to 60 years, which together with sta- an undiagnosed identifiable cause.10,11 Previous studies
bility or small decreases in diastolic BP produces the phe- suggested that primary aldosteronism and obstructive
nomenon of isolated systolic hypertension.2,20 The fact sleep apnea are particularly common in patients with
that high SBP levels is the main culprit responsible for resistant hypertension,6,45,46 and research interest has
poor control rates both in the general population of hy- turned towards the efficacy of aldosterone blockade in
pertensives and patients with diabetes or CKD,14,17,18 such individuals. A recent population study including
also supports the association between increasing age and more than 1600 individuals presenting in a tertiary
resistant hypertension. Obviously, the aging of the Wes- clinic with resistant hypertension showed that a defi-
tern populations43 will be a major factor driving the nite diagnosis of primary aldosteronism after extensive
future rise in the prevalence of hypertension (including work-up could be made in about 11% of patients.47
resistant hypertension), particularly since the frequency Although this percentage is lower than reported in
of all related conditions (eg, obesity, diabetes, CKD) also smaller studies, it clearly suggests that aldosterone
increases with advancing age.13,41,44 excess is an important cause of treatment resistance.
Another common cause of treatment resistance is Thus, in patients with resistant hypertension, the pres-
intake of pharmacologic agents that increase BP.6,20 ence of the above causes of secondary hypertension
The effect of such agents are individualized. Most should always be examined and a concerted search for
people manifest little effect, but some may experience other identifiable causes, such as renovascular disease,
severe BP elevation. Nonsteroidal anti-inflammatory pheochromocytoma, Cushing’s syndrome, hyperpara-
drugs are the most commonly used drugs of this thyroidism and hypoparathyroidism, and others
category. They increase mean BP by about 5.0 mm Hg (Table II) may be needed according to clinical and lab-
and interfere with the BP-lowering effect of several anti- oratory findings.
hypertensive drug classes through inhibition of renal
prostaglandin production with subsequent sodium and CONCLUSIONS
fluid retention, effects that may be worse in individuals The epidemiology of resistant hypertension is an
with reduced renal reserve. Use of selective cyclooxy- important but still relatively understudied field.
genase-2 inhibitors has similar effects.6,26 Sympathomi- Although the prevalence of resistant hypertension has
metic agents (nasal decongestants, anorectic pills, not been properly examined, indirect evidence from
cocaine), oral contraceptives, glucocorticoids, anabolic both population studies and clinical trials suggest that
steroids, erythropoietin, cyclosporine, and licorice it is a common clinical problem. Similarly, previous
(included in oral tobacco and herbal supplements) are data directly connecting the risk of hypertensive com-
also commonly used agents that may raise BP.6,26 plications with the level of BP and showing resistant
The presence of CKD is perhaps the most frequent hypertension to carry a higher burden of target organ
unappreciated medical cause of resistant hyperten- damage suggest that this entity has an unfavorable
sion.26 Kidney disease can be both a cause and a prognosis. Factors that produce a false impression of
consequence of hypertension. Identification of renal resistance are common in patients referred with ‘‘resis-
parenchymal disease as a cause of hypertension usually tant hypertension’’ and should be carefully excluded.
occurs only in severe cases of patients with recently However, the most important notion from an epidemi-
diagnosed hypertension. In most cases, essential hyper- ologic standpoint is that factors and conditions that
tension, which is practically the most important cause true elevations of BP (eg, excess sodium or
contributor to CKD,31 will lead to progressive renal alcohol intake, use of exogenous substances, obesity,
damage. The impaired ability to excrete sodium loads diabetes, older age, CKD, and certain identifiable
with kidney function deterioration will interfere with causes of hypertension) are not only common but in
BP control, establishing a vicious circle between many countries are also continuously increasing in
hypertension and CKD. This difficulty in achieving prevalence. These observations suggest that resistant
hypertension control is exemplified by the high num- hypertension will be a major clinical problem in the
ber of antihypertensive compounds (average, 3 or 4) future and call for additional research activities and
needed to achieve conventional BP goals in major clin- clinical focus on this particular field.
ical trials on CKD.20 Reliance on serum creatinine
measurements, which can be normal or near normal in Acknowledgments and disclosures: This paper was not supported by any
many patients with mild renal dysfunction,31 will hide source and represents an original effort. The author discloses no conflict of
interest.
this contribution of CKD in patients with resistant
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528 The Journal of Clinical Hypertension Vol 13 | No 7 | July 2011 Official Journal of the American Society of Hypertension, Inc.