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Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
DOI: 10.1161/HYPERTENSIONAHA.108.189141
2008;51;1403-1419; originally published online Apr 7, 2008; Hypertension
Keith Ferdinand, Thomas D. Giles, Bonita Falkner and Robert M. Carey
Sica,Robert D. Toto, Anthony White, William C. Cushman, William White, Domenic
David A. Calhoun, Daniel Jones, Stephen Textor, David C. Goff, Timothy P. Murphy,
Committee of the Council for High Blood Pressure Research
Statement From the American Heart Association Professional Education
Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific
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Resistant Hypertension: Diagnosis, Evaluation,
and Treatment
A Scientific Statement From the American Heart Association
Professional Education Committee of the Council for
High Blood Pressure Research
David A. Calhoun, MD, FAHA, Chair; Daniel Jones, MD, FAHA; Stephen Textor, MD, FAHA;
David C. Goff, MD, FAHA; Timothy P. Murphy, MD, FAHA; Robert D. Toto, MD, FAHA;
Anthony White, PhD; William C. Cushman, MD, FAHA; William White, MD;
Domenic Sica, MD, FAHA; Keith Ferdinand, MD; Thomas D. Giles, MD;
Bonita Falkner, MD, FAHA; Robert M. Carey, MD, MACP, FAHA
Abstract—Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the
exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30%
of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence
of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant
hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing,
severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and
chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm
persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor
medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial
in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance;
diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a
subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for
identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary
causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms
of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have
been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the
lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high
cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence
of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated
medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study
participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more
effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.
(Hypertension. 2008;51:1403-1419.)
Key Words: AHA Scientific Statements � hypertension � blood pressure
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© 2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.108.189141
1403
AHA Scientific Statement
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Resistant hypertension is defined as blood pressure thatremains above goal in spite of the concurrent use of 3
antihypertensive agents of different classes. Ideally, one of
the 3 agents should be a diuretic and all agents should be
prescribed at optimal dose amounts. Although arbitrary in
regard to the number of medications required, resistant
hypertension is thus defined in order to identify patients who
are at high risk of having reversible causes of hypertension
and/or patients who, because of persistently high blood
pressure levels, may benefit from special diagnostic and
therapeutic considerations. As defined, resistant hypertension
includes patients whose blood pressure is controlled with use
of more than 3 medications. That is, patients whose blood
pressure is controlled but require 4 or more medications to do
so should be considered resistant to treatment.
Prevalence
The prevalence of resistant hypertension is unknown. Cross-
sectional studies and hypertension outcome studies suggest,
however, that it is not uncommon. In a recent analysis of
National Health and Nutrition Examination Survey
(NHANES) participants being treated for hypertension, only
53% were controlled to �140/90 mm Hg.1 In a cross-
sectional analysis of Framingham Heart Study participants,
only 48% of treated participants were controlled to �140/
90 mm Hg and less than 40% of elderly participants (�75
years of age) were at a goal blood pressure.2 Among higher-
risk populations and, in particular, with application of the
lower goal blood pressures recommended in the Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure
(JNC 7) for patients with diabetes mellitus or chronic kidney
disease (CKD), the proportion of uncontrolled patients is
even higher. Of NHANES participants with chronic kidney
disease, only 37% were controlled to �130/80 mm Hg3 and
only 25% of participants with diabetes were controlled to
�130/85 mm Hg.1
Uncontrolled hypertension is not synonymous with resis-
tant hypertension. The former includes patients who lack
blood pressure control secondary to poor adherence and/or an
inadequate treatment regimen, as well as those with true
treatment resistance. To accurately determine the prevalence
of resistant hypertension, a forced titration study of a large,
diverse hypertensive cohort would be required. Such a study
has not been done, but recent hypertension outcome studies
offer an alternative as medications in these studies were
usually provided at no charge, adherence was closely moni-
tored, and titration of medications was dictated per protocol.
In this regard, the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT) may be
the most relevant as it included a large number of ethnically
diverse participants (�33 000): 47% female, 35% African
American, 19% Hispanic, and 36% with diabetes.4
In ALLHAT, after approximately 5 years of follow-up,
34% of participants remained uncontrolled on an average of
2 medications.5 At the study’s completion, 27% of partici-
pants were on 3 or more medications. Overall, 49% of
ALLHAT participants were controlled on 1 or 2 medications,
meaning that approximately 50% of participants would have
needed 3 or more blood pressure medications. This percent-
age, however, may underestimate the degree of treatment
resistance relative to the general hypertensive population, as
patients with a history of difficult-to-treat hypertension
(needing more than 2 medications to achieve a blood pressure
of �160/100 mm Hg) were precluded from enrolling in
ALLHAT. Conversely, this percentage might overestimate
the prevalence of resistant hypertension as a consequence of
the restricted treatment regimens allowed in ALLHAT. Com-
bined use of any 2 of the following classes of medications
was discouraged: thiazide-type diuretics, angiotensin-
converting enzyme (ACE) inhibitors, calcium channel block-
ers, and � adrenergic receptor antagonists. Such combina-
tions account for a substantial proportion of current clinical
practice.
Prognosis
The prognosis of patients with resistant hypertension com-
pared with patients with more easily controlled hypertension
has not been specifically evaluated. Presumably, prognosis is
impaired as such patients typically present with a long-
standing history of poorly controlled hypertension and com-
monly have associated cardiovascular risk factors such as
diabetes, obstructive sleep apnea, left ventricular hypertrophy
(LVH), and/or CKD. The degree to which cardiovascular risk
is reduced with treatment of resistant hypertension is un-
known. The benefits of successful treatment, however, are
likely substantial as suggested by hypertension outcome
studies in general and by the early Veterans Administration
cooperative studies, which demonstrated a 96% reduction in
cardiovascular events over 18 months with use of triple
antihypertensive regimens compared with placebo in patients
with severe hypertension (diastolic blood pressure 115 to
129 mm Hg).6 How much of this benefit occurs with success-
ful treatment of resistant hypertension is unknown.
Patient Characteristics
Blood pressure remains uncontrolled most often because of
persistent elevations in systolic blood pressure. Among Fra-
mingham participants being treated for hypertension, 90%
had achieved a diastolic blood pressure goal of �90 mm Hg,
while only 49% were at a systolic blood pressure goal of
�140 mm Hg.2 This disparity in systolic versus diastolic
blood pressure control worsened with increasing age such
that systolic control rates exceeded 60% for younger partic-
ipants (�60 years) but was �40% in older subjects (�75
years). Prospectively, ALLHAT demonstrated a similar dif-
ficulty in controlling systolic blood pressure in that only 67%
of the participants had their systolic blood pressure lowered
to �140 mm Hg, whereas 92% of participants achieved a
goal diastolic blood pressure of �90 mm Hg.5
In an analysis of Framingham study data, the strongest
predictor of lack of blood pressure control was older age, with
participants �75 years being less than one fourth as likely to
have systolic blood pressure controlled compared with par-
ticipants �60 years of age.2 The next strongest predictors of
lack of systolic blood pressure control were the presence of
1404 Hypertension June 2008
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LVH and obesity (body mass index [BMI]�30 kg/m2) (Table
1). In terms of diastolic blood pressure control, the strongest
negative predictor was obesity, with blood pressure being
controlled about one third less often compared with lean
participants (BMI �25 kg/m2). In a prospective analysis of
Framingham participants, in addition to older age, higher
baseline systolic blood pressure was associated with in-
creased risk of never reaching goal blood pressure.7
In ALLHAT, older age, higher baseline systolic blood
pressure, LVH, and obesity all predicted treatment resistance
as defined by needing 2 or more antihypertensive medica-
tions.5 Overall, the strongest predictor of treatment resistance
was having CKD as defined by a serum creatinine of �1.5
mg/dL. Other predictors of the need for multiple medications
included having diabetes mellitus and living in the southeast-
ern United States. African-American participants had more
treatment resistance, as did women, such that black women
had the lowest control rate (59%) and non-black men the
highest (70%).
Although the exact prevalence is unknown, the above
studies indicate that resistant hypertension is a common
clinical problem. Further, with a progressively older and
heavier population in association with an increasing inci-
dence of diabetes and CKD, the prevalence of resistant
hypertension can be anticipated to increase.
Genetics/Pharmacogenetics
As resistant hypertension represents an extreme phenotype, it
seems reasonable to predict that genetic factors may play a
greater role than in the general hypertensive population.
However, genetic assessments of patients with resistant
hypertension are limited. In one of the few genetic evalua-
tions of patients with resistant hypertension, investigators in
Finland screened 347 patients with resistant hypertension for
mutations of the � and � subunits of the epithelial sodium
channel (ENaC).8 Mutations of these subunits can cause
Liddle’s syndrome, a rare monogenic form of hypertension.
Compared with normotensive controls, 2 � ENaC and �
ENaC gene variants were significantly more prevalent in the
patients with resistant hypertension. The presence of the gene
variants was associated with increased urinary potassium
excretion relative to plasma renin levels but was not related to
baseline plasma aldosterone or plasma renin activity. In
addition, when inserted into Xenopus oocytes, the most
commonly used expression system for ENaC functional
studies, the gene variants did not show a significant differ-
ence in activity compared with ENaC wild-type, arguing
against clinically meaningful effects for these mutations.
The CYP3A5 enzyme (11�-hydroxysteroid dehydrogenase
type 2) plays an important role in the metabolism of cortisol
and corticosterone, particularly in the kidney. A particular
CYP3A5 allele (CYP3A5*1) has been associated in African-
American patients with higher systolic blood pressure levels
in normotensive participants9 and hypertension more resistant
to treatment.10 Although based on a very small number of
patients, these results are provocative and support additional
attempts to identify genotypes that may relate to treatment
resistance. Identification of genetic influences on resistance
to current therapies might also lead to development of new
therapeutic targets.
Pseudoresistance
Poor Blood Pressure Technique
Inaccurate measurement of blood pressure can result in the
appearance of treatment resistance. Two of the most common
mistakes—measuring the blood pressure before letting the
patient sit quietly and use of too small a cuff—will result in
falsely high blood pressure readings.11 Although the degree to
which inaccurate measurement of blood pressure results in
falsely labeling patients as having uncontrolled hypertension
is unknown, assessments of office blood pressure measure-
ment technique suggest that it is likely a common clinical
problem.11
Poor Adherence
Poor adherence to antihypertensive therapy is a major cause
of lack of blood pressure control.12 Retrospective analyses
indicate that approximately 40% of patients with newly
diagnosed hypertension will discontinue their antihyperten-
sive medications during the first year of treatment.13,14 During
5 to 10 years of follow-up, less than 40% of patients may
persist with their prescribed antihypertensive treatment.13,15
While poor adherence is common at the primary care level, it
may be less common among patients who are seen by
specialists. In a retrospective analysis at a hypertension
specialty clinic, it was estimated that poor adherence was a
significant contributing factor to the lack of blood pressure
control in only 16% of evaluated patients.16
Lack of blood pressure control is distinct from treatment
resistance. For an antihypertensive regimen to have failed, it
has to have been taken correctly. This distinction is clinically
important as patients with poorly controlled hypertension
secondary to lack of adherence need not be subjected to the
evaluations and continued manipulations in treatment regi-
mens that are undertaken for patients with true treatment
resistance.
White-Coat Effect
Studies indicate that a significant white-coat effect (when
clinic blood pressures are persistently elevated while out-of-
Table 1. Patient Characteristics Associated With Resistant
Hypertension
Older age
High baseline blood pressure
Obesity
Excessive dietary salt ingestion
Chronic kidney disease
Diabetes
Left ventricular hypertrophy
Black race
Female sex
Residence in southeastern United States
Calhoun et al Resistant Hypertension 1405
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office values are normal or significantly lower) is as common
in patients with resistant hypertension as in the more general
hypertensive population, with a prevalence in the range of
20% to 30%.17,18 Also, as with more general hypertensive
patients, patients with resistant hypertension on the basis of a
“white coat” phenomenon manifest less severe target organ
damage and appear to be at less cardiovascular risk compared
with those patients with persistent hypertension during am-
bulatory monitoring.19–21
Lifestyle Factors
Obesity
Obesity is associated with more severe hypertension, a need
for an increased number of antihypertensive medications, and
an increased likelihood of never achieving blood pressure
control.5,22 As a consequence, obesity is a common feature of
patients with resistant hypertension.23 Mechanisms of
obesity-induced hypertension are complex and not fully
elucidated but include impaired sodium excretion, increased
sympathetic nervous system activity, and activation of the
renin-angiotensin-aldosterone system.24
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