Editorial
Resistant Hypertension: An Update
David A. Calhoun,1 Ernesto L. Schiffrin,2 and John M. Flack3
With the recent publication of the
revised American Heart Association
(AHA) Scientific Statement on Resistant
Hypertension: Detection, Evaluation,
and Management as well as other critical
documents, major advances have been
in our in how resistant hypertension
(RHTN) and is defined, diagnosed, and
best treated as well as our understanding
of the pathophysiology of RHTN.1 The
new Scientific Statement is important
in defining RHTN much more
comprehensively than simply based on
the blood pressure (BP) level and number
of prescribed medications as it has been
expanded to incorporate exclusion of
common pseudocauses of treatment
resistance, specifically inaccurate BP
measurement, a prominent white-
coat effect, undertreatment, and
poor medication adherence. The new
American College of Cardiology (ACC)/
AHA hypertension guidelines are
important in providing a preliminary
estimate of the prevalence of RHTN
based on the now lower recommended
BP goal of 130/80  mm Hg.2 The
landmark PATHWAY-2 study adds
importantly to our understanding of the
pathophysiology of RHTN and provides
compelling evidence for the most
Correspondence: David A. Calhoun (dcalhoun@
uab.edu).
1Department of Medicine, Vascular Biology and
Hypertension Program, University of Alabama
at Birmingham, Birmingham, Alabama,
USA; 2Lady Davis Institute of Medical Research,
and Department of Medicine, Sir Mortimer
B. Davis-Jewish General Hospital, McGill
University, Montreal, Quebec, Canada; 3Division
of General Medicine, Hypertension Section,
Department of Medicine, Springfield, Illinois,
USA. 
Initially submitted October 14, 2018; accepted
for publication October 15, 2018; online
publication November 8, 2018.
doi:10.1093/ajh/hpy156
© American Journal of Hypertension, Ltd
2018. All rights reserved. For Permissions,
please email: journals.permissions@oup.com
effective multiple-drug combination for
treating RHTN, including especially,
preferential use of spironolactone.3 This
editorial serves to highlight these recent
advances.
DEFINTION
The revised AHA Statement defines
RHTN as “…the BP of a hypertensive
patient that remains elevated above
goal despite the concurrent use of 3
antihypertensive agents of different
classes, commonly including a long-
acting calcium channel blocker (CCB), a
blocker of the renin-angiotensin system
(angiotensin converting enzyme [ACE]
inhibitor or angiotensin receptor blocker
[ARB]), and a diuretic. All agents
should be administered at maximum
or maximally tolerated doses and at the
appropriate dosing frequency.”1 This part
of the definition is largely the same as
the prior AHA definition in stating that
RHTN is BP above goal in spite of use
of 3 or more antihypertensive agents of
different classes, at maximally tolerated
doses.4 The revised definition, however,
goes further than the prior definition
in suggesting that the first 3 agents, if
possible, should be comprised specifically
of an ACE inhibitor or ARB, a CCB, and
a diuretic. Although the rational for the
recommendation of this standardized
triple regimen is not provided in detail, it
is no doubt based on (i) the recognition
that the these 3 classes of agents are
complimentary in their mechanisms
of action, (ii) the antihypertensive
efficacy of these classes of agents is
well established, (iii) all of the classes
of agents are available in long-acting,
generic formulations, (iv) individual
agents within each of the 3 classes are
generally well tolerated and safe, (v) and
agents from these classes are available
in dual and even triple combinations
allowing for simplification of dosing and
potentially lower out-of-pocket costs for
patients. The document does specifically
recommend use of dihydropyridine
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CCBs, i.e., amlodipine and nifedipine,
because they have been much more
widely used than non-dihydropyridine
CCBs, i.e., diltiazem and verapamil, in
studies of RHTN, particularly, in studies
establishing the benefit of spironolactone
for treatment of RHTN. The statement
also indicates that the diuretic used
in this standardized triple regimen
should, in most patients, be a thiazide
or thiazide-like diuretic. It does not
specify preferential use of chlorthalidone
over hydrochlorothiazide  (HCTZ) for
initial use but changing from HCTZ
to chlorthalidone is recommended
as part of the treatment algorithm
if the BP remains uncontrolled. The
statement further indicates that HCTZ
will provide diminishing benefit as
the estimated glomerular filtration
rate  (eGFR) declines below 45  ml/
min−1/1.73  min−2, while chlorthalidone
can be effective with eGFRs down to
25–30  ml/min−1/1.73  min−2. Below
this level eGFR or in hypoalbuminuric
states (serum albumin <3.0 g/l), a long-
acting loop diuretic such as torsemide is
recommended.1
Importantly, the revised definition is
different than the prior AHA definition
in that it specifically requires exclusion
of so-called pseudocauses of treatment
resistance, i.e., poor BP measurement
technique, white-coat effect, and poor
medication adherence before diagnosing
RHTN.1 Incorporation of these
requirements into the definition of RHTN
is based on the growing recognition that
pseudocauses of treatment resistance
are common and must to accounted
for, as much as possible, to confirm true
treatment resistance.
In summary, the definition of RHTN
has been expanded beyond the 2008
definition to specifically require (i) BP
above goal despite concurrent use of
3 or more antihypertensive agents at
maximum or maximally tolerated doses,
including, if possible, a ACE inhibitor
or ARB, a CCB, and a diuretic, (ii)
measurement of BP according to clinical
American Journal of Hypertension  1
Editorial
practice guidelines, (iii) exclusion of a
white-coat effect, (iv) exclusion of poor
antihypertensive medication adherence.1
Accordingly, the current definition
of RHTN is more comprehensive in
standardizing the initial 3 drug regimen
and in requiring exclusion of common
causes of pseudotreatment resistance.
The revised definition will better
distinguish true treatment resistance
from the much larger category of
uncontrolled hypertension attributable
to undertreatment, including
underdosing and/or use of ineffective
drug combinations; falsely elevated BP
readings because of poor BP measuring
technique; a large white-coat effect; and
poor medication adherence. However,
application of the revised definition will
engender challenges for clinicians in
requiring lengthier and more systematic
assessments of office BP, use of reliable
and affordable methods for determining
out-of-office BP levels, and access to
accurate determinations of medication
adherence.
PREVALENCE
Application of the new definition of
RHTN in combination with the lower
BP goal of 130/80 mm Hg included in the
2017 American College of Cardiology
ACC/AHA Hypertension Guidelines
will result in a higher prevalence of
RHTN. Although unreferenced, in the
ACC/AHA document, it was estimated
that the prevalence of RHTN will
increase by about 4% with use of the
lower BP goals.2 Although this intuitively
may seem like an underestimate based
on the much lower BP threshold, upon
consideration, this small change makes
sense in that the only group of patients
whose categorization changes is those
patients whose BP had been previously
controlled between 130–139/80–89 mm
Hg on 3 medications. Based on the
old BP threshold of 140/90  mm Hg,
such patients did not have RHTN
because they were controlled with 3
medications, but because of the lower
BP threshold, they are now uncontrolled
on 3 medications and fulfill the current
definition of RHTN. Patients controlled
to less than 130/80 mm Hg on 3 or more
medications still have controlled RHTN
by the prior and current definition, while
patients with a BP >140/90 still have
2  American Journal of Hypertension
uncontrolled RHTN by both definitions.
Accordingly, while the change in
prevalence of RHTN with application of
the revised definition has not yet been
rigorously determined, a 4% increase is
likely correct as the only relevant change
will be in the narrow group of patients
whose BP is 130–139/80–89 mm Hg on
3 medications, who now have RHTN
based on the revised definition.
An earlier study of patients referred
to a hypertension specialty reported an
overall prevalence of RHTN within their
clinic of 14.7%.5 Importantly however,
during a median follow-up period of
7  months, the period prevalence had
increased up to 43.6%. This dramatic
increase in the prevalence of RHTN
within this specialty clinic was because
of continued up-titration of existing
medications along with the addition
of new ones. With intensification of
treatment, many additional patients
met criteria for having RHTN. These
findings indicate that cross-sectional
of community-based cohorts likely
underestimate the true prevalence of
RHTN as many patients remained
undertreated, falsely lowering the
prevalence of apparent RHTN.
PHARMCOLOGIC TREATMENT
Perhaps the most important finding
since publication of the 2008 Scientific
Statement has been the clear confir-
mation of spironolactone as the most
appropriate fourth agent for treating
RHTN. The original 2008 Scientific
Statement on RHTN included a
strong recommendation for adding
spironolactone after the first 3
medications, but this recommendation
was largely based on observational
data or open-label assessments of
spironolactone.4 Absent at the time
was rigorous demonstration of the
superiority of spironolactone for treating
RHTN compared with other classes of
antihypertensive agents. In 2015, this
deficiency was overcome with publication
of the PATHWAY-2 study.3 In this
landmark study, the antihypertensive
benefit of placebo, spironolactone
25–50 mg daily, a β-blocker (bisoprolol
10–20 mg), and an α-blocker (doxazosin
4–8  mg) were compared in a double-
blind, randomized study design in
patients uncontrolled on a standardized
regimen of an ACE inhibitor or an ARB,
amlodipine, and indapamide. After
3 months of treatment with each agent,
spironolactone was clearly superior to
placebo and the 2 active agents, with
spironolactone reducing home systolic
BP by 8.7  mm Hg more than placebo,
4.5  mm Hg more than bisoprolol, and
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4.0  mm Hg more than doxazosin. The
percentage of patients whose BP was
controlled was 58.0% for spironolactone
compared with 23.9% for placebo, 43.3%
for bisoprolol, and 41.5% for doxazosin.
These findings clearly establish
spironolactone as the most appropri-
ate fourth agent to be used if a patient’s
BP remains above goal on the standard
triple regimen of an ACE inhibitor or
ARB, amlodipine, and chlorthalidone or
indapamide, a regimen consistent with
that recommended in the new ACC/
AHA guidelines.
The PATHWAY-2 study provided 2
additional findings that are clinically
relevant for treating RHTN. Firstly,
prior studies evaluating the effectiveness
of spironolactone for treating RHTN
were largely limited to a maximum daily
dose of 25  mg. PATHWAY-2, however,
demonstrated that spironolactone
50  mg daily provided as much addi-
tional benefit as the initial starting dose
of 25 mg, i.e., the antihypertensive ben-
efit was almost equally divided between
the 25 and 50  mg doses.3 This clear
demonstration of continued benefit
provides important demonstration of an
effective dose range for spironolactone
up to at least 50  mg daily for treating
RHTN. As the dose benefit had clearly
not plateaued, additional studies to
determine whether further benefit is
accrued with titration of spironolactone
above 50 mg seem warranted.
The other important finding from
PATHWAY-2 was demonstration of the
enhanced benefit of spironolactone in
patients with suppressed renin levels.3
While spironolactone was more effective
than the other 2 agents across the entire
range of renin levels, patients with
suppressed renin manifested especially
large benefit, with mean home systolic
BP reductions exceeding 20  mm Hg.
This is an extraordinary degree of benefit
from a single antihypertensive agent and
is seemingly unique in being predicted
by a routine biochemical assessment.
The ability of suppressed renin levels

(or plasma renin activity) to predict
the BP response to spironolactone cer-
tainly supports assessing renin levels or
renin activity in all patients with RHTN
but raises the question if suppressed
renin levels might also more predict
the BP response to spironolactone
in hypertensive patients in general.
If so, it suggests the potentially far-
reaching possibility of targeting initial
drug selection based on a simple and
inexpensive biochemical test.
PATHOPHYSIOLOGY
PATHWAY-2 included 3 substudies
that likewise yielded important clinical
findings regarding treatment of RHTN.
In the first substudy, the BP response to
spironolactone was related to baseline
renin levels, plasma aldosterone levels,
and the ratio of plasma aldosterone and
renin concentration.6 A  high aldos-
terone and renin concentration and a
low renin level both strongly predicted
a large BP response to spironolactone,
with the former being overall slightly
better. In contrast, plasma aldoste-
rone was positive but weakly related
to spironolactone-induced changes in
BP. In the second substudy, the effect
of the 3 different agents on thoracic
fluid content, an index of volume
status, was determined.6 Bisoprolol,
the β-blocker, had no effect on thoracic
fluid content, while doxazosin, the
α-antagonist, increased it, indicating
increased fluid retention. In contrast,
spironolactone reduced thoracic fluid
content by about 7%, consistent with
a significant reduction in intravascular
fluid retention. Combined, these 2
PATWAY-2 substudy results strongly
implicate inappropriate fluid retention
attributable to varying degrees of
hyperaldosteronism as a broad
mediator of antihypertensive treatment
resistance. The results of the earlier
main PATHWAY-2 are consistent with
this underlying pathophysiology in
demonstrating that this fluid retention
is best overcome by the natuiretic and
diuretic effects of spironolactone.
Lastly, the third PATWAY-2 substudy
assessed the benefit of amiloride for
treating RHTN.6 After completion of the
blinded protocol, participants willing to
continue were crossed over to amiloride
10–20 mg daily for 6–12 weeks. After 6
weeks, amiloride 10 mg had reduced the
home systolic BP by 20.4 mm Hg, which
was slightly better than the 18.3 mm Hg
observed with spironolactone 25  mg.
In patients uncontrolled on amiloride
10 mg after 6 weeks and so titrated up to
20 mg, a similar dose-response as with
spironolactone 25–50 mg was observed.
While not as rigorous as the evaluation
of spironolactone because of its open-
label assessment, the findings do provide
compelling rationale for considering
amiloride as an effective alternative to
spironolactone, especially if the latter is
not tolerated.
In summary, since publication of
the 2008 AHA Scientific Statement on
RHTN, important advances in how
we diagnose and treatment RHN have
occurred. Firstly, with the recent revision
of the AHA Scientific Statement, the
importance of accounting for common
pseudocauses of RHTN is emphasized
by incorporating into the definition use
of proper BP technique to ensure accu-
rate BP measurement, confirmation of
uncontrolled out-of-office BP with use
of home or ambulatory BP assessments,
and ensuring adequate medication
adherence. Secondly, the 2017 ACC/
AHA Hypertension Guidelines provide a
preliminary, but important, estimate that
the lower goal BP of 130/80 mm Hg will
only increase the prevalence of RHTN by
the relatively modest amount of about 4%.
Lastly, with publication of the PATHWAY-2
study and accompanying substudies,
RHTN was shown be broadly attribut-
able to excess fluid retention secondary
varying degrees of hyperaldosteronism
that is most effectively overcome by use of
spironolactone, or alternatively, amiloride.
ACKNOWLEDGMENT
Dr Calhoun received grant support
from ReCor Medical (NCT02649426),
and Dr Flack received grant support from
ReCor Medical (NCT02649426) and
Vascular Dynamics (NCT03179800).
DISCLOSURE
Dr Calhoun is a consultant for
Selenity Therapeutics,  and Idorsia
Editorial
Pharmaceuticals. Flack is a consultant
for Back Beat Hypertension.
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American Journal of Hypertension  3