Download Resistant Hypertension

supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
17
Resistant Hypertension
Sanjeev Gulati*, Shrea Gulati**
Introduction
R
esistant hypertension is a common
clinical problem faced by both primary
care clinicians and specialists. The exact
prevalence of resistant hypertension is
unknown. In various studies its prevalence
has been reported to be 20% to 30% of
study participants.1
However, before we label a patient
as resistant hypertension it is important
to ensure that we follow the standard
guidelines for measuring blood pressure
in our patients. These state that:
•
Case Definitions
Proper blood pressure measurement
technique must be used
•
It is important to clearly understand
and differentiate resistant hypertension
from others.
The size of the blood pressure
cuff should be double checked for
accuracy
•
The blood pressure readings must be
recorded on 2 separate occasions
a.Resistant hypertension : Resistant
hypertension is defined in the
2008 American Heart Association
scientific statement as blood
pressure that remains above goal
in spite of concurrent use of three
antihypertensive agents of different
classes. 1
b.R e f r a c t o r y h y p e r t e n s i o n : S o m e
patients with resistant hypertension
cannot be controlled, even with
maximal medical therapy (four or
more drugs with complementary
mechanisms given at maximal
tolerated doses) under the care
of a hypertension specialist. Such
patients are referred to as having
refractory hypertension. Non
responsiveness in such patients may
be due to neurologic mechanisms
(e.g., sympathetic overactivity).
*
Director, Nephrology, Fortis
Institute of Renal Sciences and
Transplantation, Vasant Kunj,
New Delhi; **Third Year Resident
at All India Institute of Medical
Sciences, Delhi.
resistant to treatment but is actually
attributable to other factors.
c. Apparent resistant hypertension
: Patients with apparent resistant
hypertension have uncontrolled
clinic blood pressure (i.e., greater
t h a n or e q u a l t o 1 4 0 / 9 0 mmH g )
despite being prescribed three or
more antihypertensive medications,
or require prescriptions of four
or more drugs to control their
blood pressure. 2,3 However, such
patients may have pseudoresistant
hypertension.
d. P s e u d o r e s i s t a n t h y p e r t e n s i o n :
Pseudoresistance refers to poorly
controlled hypertension that appears
The measurement of blood pressure
should be conducted after a patient has
been seated quietly for 5 minutes and
his or her arm should be at heart level.
Then, using a properly calibrated and
appropriately sized cuff, blood pressure
should be measured. Too narrow or too
short a cuff may give an erroneously high
reading (usually more than 5–15 mmHg
elevation in case of systolic pressure). The
patient should be encouraged to avoid
smoking before 15–30 min of the blood
pressure measurement, because smoking
may elevate systolic blood pressure up
to 5–20 mmHg. It is also suggested to
avoid drinking of coffee, although this
may cause only a small elevation in blood
pressure.
True resistant hypertension – Patients
with true resistant hypertension are
those who have uncontrolled clinic blood
pressure despite being compliant with an
antihypertensive regimen that includes
three or more drugs (including a diuretic,
and each at optimal doses i.e., 50 percent
or more of the maximum recommended
antihypertensive dose), and who also have
uncontrolled blood pressure confirmed
by 24-hour ambulatory blood pressure
monitoring. Pressure is controlled with
four or more medications should be
considered to have resistant hypertension.
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
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supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
Table 1 : General characteristics of patients with resistant
hypertension
•
Old age
•
Female Sex
•
Smoking
•
Excessive Salt Consumption
•
Chronic Consumption of Interfering Drugs (NSAIDs, steroids,
etc)
•
Obesity
•
High baseline Blood Pressure (BP)
•
Chronic Kidney Disease (CKD)
•
Diabetes Mellitus
•
Left Ventricular Hypertrophy
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. Resistant hypertension
is not synonymous with uncontrolled hypertension
since resistant hypertension is not the only cause
of uncontrolled hypertension. Other causes include
inadequate treatment regimens and pseudoresistance.
The five most common causes of pseudoresistance are:
1.Inaccurate measurement of blood pressure (e.g.,
use of an inappropriately small blood pressure
cuff).
2. Poor adherence to antihypertensive therapy. In
one study, for example, 40 out of 76 patients
with unexplained resistance to four or more
antihypertensive drugs were determined to be
either nonadherent or only partially adherent
to therapy. 4 Poor adherence to therapy is a
common cause of apparent treatment resistance.
Retrospective cohort studies suggest that ~0% of
patients with newly diagnosed hypertension will
discontinue treatment during the first year, and
only 40% will continue with therapy during the
first 5 or 10 years of follow-up. 5,6
3.Suboptimal antihypertensive therapy. In a large
series of 468,877 patients seen in an outpatient
clinic, 44,684 (9.5 percent) had apparent resistant
hypertension. 4 Of these, however, only 22,189 (half
of those with apparent resistant hypertension)
were prescribed optimal antihypertensive therapy
(defined as a diuretic and two or more additional
drugs, each at 50 percent or more of the maximal
r e c o m m e n d e d a n t i h y p e r t e n s i ve d o s e ) . Tw o
additional causes of pseudo-resistance are related
to the antihypertensive regimen itself:
a. inappropriate combinations of agents
b. clinician inertia, a failure to change or increase
dose regimens in order to obtain adequate
treatment of poorly controlled hypertension
despite awareness of the condition
4. Poor adherence to lifestyle and dietary approaches
such as a reduced sodium intake. An increased salt
intake is one of the commonest causes of apparent
treatment resistance in our day to day practice.
5. White coat hypertension: White coat hypertension
(also called isolated clinic or office hypertension)
refers to patients who have office readings that
average more than 140/90 mmHg and reliable out
of office readings that average less than 140/90
mmHg. Having the BP in the office taken by a
nurse or technician, rather than the physician,
may minimise the white coat effect. White coat
hypertension is present in as many as 20 to
30 percent of patients, possibly leading to an
erroneous diagnosis of either hypertension or,
in a patient with known hypertension, resistant
disease. It is more common among patients with
resistant hypertension.
Prevalence
The exact prevalence of resistant hypertension is
unknown. This is in part due to the non-feasibility
of conducting a large, forced titration study to
answer this question appropriately. However crosssectional studies and hypertension outcome studies
suggest that it is not uncommon. Data from the
National Health and Nutrition Examination Survey
(NHANES) from 2003 to 2008 suggest that 12.8% of
the antihypertensive-treated population meets the
criteria for resistant hypertension; 8 this number may
rise to > 50% in patients with kidney diseases. 9 In
a study of 300 hypertensive chronic kidney disease
(CKD) patients, 38% met the definition of resistant
hypertension after 6 months of blood pressure
management, with a higher prevalence of diabetic
nephropathy and higher levels of proteinuria emerging
among the patients with resistant hypertension. 9,10 A
number of factors may contribute to the pathogenesis
and higher prevalence of resistant hypertension in
CKD, including impaired sodium handling, increased
activity of the renin-angiotensin-aldosterone (RAAS)
and sympathetic systems, impaired nitric oxide
synthesis and endothelium-mediated vasodilation,
and increased arterial stiffness (Table 1). 10
Genetics/Pharmacogenetics
As resistant hypertension represents an extreme
phenotype, it seems reasonable to predict that genetic
factors may play a greater role in these patients than
in the general hypertensive population. However,
genetic studies of patients with resistant hypertension
are limited. In one of the few studies of patients with
resistant hypertension in Finland, 347 patients with
resistant hypertension were screened for mutations of
the β and γ 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 β ENaC
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
19
and γ 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.
nonsteroidal anti-inflammatory agents (NSAIDs),
aspirin, and acetaminophen and, are probably the
most common offending agents in terms of worsening
blood pressure control. Meta-analyses of the effects
of NSAIDs have indicated average increases in mean
arterial pressure of approximately 5.0 mm Hg. 13
The CYP3A5 enzyme (11β-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
participants 9 and hypertension more resistant to
treatment. 11 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.
Other medication classes that may worsen blood
pressure control include antituberculous therapy and
sympathomimetic compounds such as decongestants
and certain diet pills, amphetamine-like stimulants,
modafinil, 39 and oral contraceptives. Glucocorticoids,
such as prednisone, induce sodium and fluid retention
and can result in significant increases in blood
pressure. Herbal preparations containing ephedra (or
ma huang) have been associated with worsening blood
pressure. Licorice, a common ingredient in oral tobacco
products, can raise blood pressure by suppressing
the metabolism of cortisol, resulting in increased
stimulation of the mineralocorticoid receptor. In
anaemic patients with CKD, erythropoietin therapy
may increase blood pressure in both normotensive
and hypertensive patients.
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. 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-angiotensinaldosterone system. 12
Dietary Salt
Excessive dietary sodium intake contributes to the
development of resistant hypertension both through
directly increasing blood pressure and by blunting
the blood pressure–lowering effect of most classes
of antihypertensive agents. In an analysis of patients
referred to a university hypertension centre for
resistant hypertension, average dietary salt ingestion
based on 24-hour urinary sodium excretion exceeded
10 g a day. 1
Alcohol
Heavy alcohol intake is associated with both an
increased risk of hypertension, as well as treatmentresistant hypertension. Prospectively, cessation of
heavy alcohol ingestion by a small group of patients
reduced 24-hour ambulatory systolic blood pressure
by 7.2 mm Hg and diastolic blood pressure by 6.6 mm
Hg while dropping the prevalence of hypertension
from 42% to 12%. 1
Drug-Related Causes
Several classes of pharmacological agents can
increase blood pressure and contribute to treatment
resistance. Nonnarcotic analgesics, including
Evaluation
The evaluation of patients with resistant
hypertension should be directed toward confirming
true treatment resistance; identification of causes
contributing to treatment resistance, including
secondary causes of hypertension; and documentation
of target-organ damage. Accurate assessment of
treatment adherence and use of good blood pressure
measurement technique is required to exclude
pseudoresistance. In most cases, treatment resistance
is multifactorial in aetiology with obesity, excessive
dietary sodium intake, obstructive sleep apnoea, and
CKD being particularly common factors. Target-organ
damage such as retinopathy, CKD, and LVH supports
a diagnosis of poorly controlled hypertension and
in the case of CKD will influence treatment in terms
of classes of agents selected as well as establishing a
blood pressure goal of < 140/90 mm Hg. 14
ABPM and resistant hypertension
Confirmation of true resistant hypertension should
include the accurate measurement of office blood
pressure, with attention to environment, body and arm
position, appropriate cuffs, and the recommendation
that multiple measurements be obtained at least 1
min apart and averaged out. Use of clinic blood
pressure measurements has shortcomings. Hence
for the diagnosis of Resistant hypertension it is
absolutely essential that the clinician uses out-of-office
monitoring including home and 24-h ambulatory
blood pressure monitoring (ABPM).
ABPM, which involves readings taken at preset
intervals throughout the day and night to capture
the diurnal rhythm and variability of blood pressure
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supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
over 24 h, can help detect ‘white-coat’ hypertension,
an elevation in blood pressure that occurs during
clinic visits, with normal blood pressure in non-clinic
settings and absence of target organ damage. 15 The
confirmation of white-coat hypertension, a common
cause of pseudo-resistance, identifies patients who are
relatively low risk and therefore unlikely to benefit
from additional antihypertensive therapy. In one study
of patients with apparent resistant hypertension, 28%
were found to have normal awake ambulatory blood
pressure when ABPM was used to complement office
BP measurements. 16
Twenty-four-hour ABPM has, in fact, been shown
to be the best method for estimating a patient’s
hypertension-related cardiovascular risk. 17 ABPM can
identify patients with ‘masked’ hypertension, (elevated
ambulatory blood pressure but normal clinic blood
pressure), and has been associated with an increased
risk of cardiovascular events. In a study of 466 patients
with apparent responder hypertension based on clinic
measurements, ambulatory BP monitoring found 27%
to have ‘masked’ hypertension, which over a follow-up
period of 5 years was associated with a relative
risk of 2.28 (95% CI, 1.1–4.7; P < 0.05) of fatal and
nonfatal cardiovascular events, compared with true
responder hypertension. Moreover, ABPM provides
clinicians with the ability to capture nighttime blood
pressures and to identify the presence of a ‘nondipping’ pattern, which is the diminution or reversal
of the normal 10–20% nocturnal fall in blood pressure
that occurs in both normotensive and hypertensive
individuals. Several studies have shown that both
of these are independent CVS risk factors. ABPM
takes on greater importance in the CKD population
with hypertension, as both non-dipping and masked
hypertension are more common among patients with
CKD. In the AASK Cohort Study, a remarkable 80%
of the participants were non-dippers, and of the
377 participants with controlled clinic BP, 70% had
masked hypertension. 18 Higher nighttime BP and
masked hypertension were associated with increased
severity of target organ damage, including higher
prevalence of left ventricular hypertrophy (LVH) and
proteinuria and lower estimated GFR. Accordingly,
in a large cohort of 436 hypertensive patients with
CKD, ABPM has been shown to be a better predictor
of renal and cardiovascular end points compared with
office BP measurements, the components of ABPM. 19
As this study suggests, the prognostic role of ABPM
is superior to that of office BP among CKD patients.
Investigations and Laboratory evaluation
Basic laboratory testing in patients with resistant
hypertension includes measurement of serum
electrolytes, glucose, and creatinine, and a urinalysis
with estimation of proteinuria (e.g., urine albuminto-creatinine ratio).
Screening for primary aldosteronism is also
warranted since, in a large series of 1616 patients with
resistant hypertension, 11 percent fulfilled criteria for
primary aldosteronism, only 46 percent of whom were
hypokalaemic. 20 Screening for primary aldosteronism
begins with a paired, morning measurement of the
plasma aldosterone concentration (PAC) and plasma
renin activity (PRA) to determine whether the patient
has an elevated or high-normal PAC, suppressed PRA,
and elevated PAC/PRA ratio. Certain antihypertensive
drugs can alter the ratio, some of which should be
discontinued prior to testing. If the ratio suggests
primary aldosteronism, further evaluation is necessary
to confirm the diagnosis. These issues are discussed
in detail elsewhere.
In addition to blood testing, a 24-hour urine
collection should be obtained on the patient’s usual
diet for determination of sodium excretion, creatinine
clearance, and aldosterone excretion. Urinary sodium
excretion permits estimation of dietary sodium intake
unless the patient has been recently (within the past
two weeks) started on a diuretic or there has been a
recent dose increase.
Pa t i e n t s w i t h r e s i s t a n t h y p e r t e n s i o n s h o u l d
also be evaluated for phaeochromocytoma if they
have suggestive manifestations such as episodic
hypertension, palpitations and/or diaphoresis, or
tremor. Noninvasive imaging — Most patients with
resistant hypertension should undergo noninvasive
imaging for renal artery stenosis. This is particularly
important in patients with known atherosclerotic
disease in other vascular beds, including peripheral
artery disease, coronary artery disease or
cerebrovascular disease, an abdominal bruit, a rise
in serum creatinine after initiation of an angiotensin
converting enzyme inhibitor or angiotensin II receptor
blocker, or, onset of hypertension at a young age which
could represent fibromuscular dysplasia.
Among patients with resistant hypertension who
have none of these risk factors, we delay screening
for renovascular disease until the remainder of the
evaluation for resistant hypertension is negative.
The preferred methods of screening are discussed
elsewhere. Because of low specificity, imaging
studies should not be performed to screen for adrenal
adenomas in the absence of biochemical evidence of
hormonally active tumours.
Treatment Recommendations
Resistant hypertension is almost always
multifactorial in aetiology. Treatment is predicated
on identification and reversal of lifestyle factors
contributing to treatment resistance; accurate
diagnosis and appropriate treatment of secondary
causes of hypertension; and use of effective multidrug regimens. When primary aldosteronism,
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
phaeochromocytoma, or Cushing’s disease is suspected
or confirmed, treatment will be specific for that
particular disorder. Treatment of sleep apnoea with
continuous positive airway pressure (CPAP) likely
improves blood pressure control.
In chronic kidney disease, the approach to treatment
of resistant hypertension should aim to address the
multitude of factors that contribute to the pathogenesis
of hypertension in this population, including
impaired handling of sodium and volume expansion,
increased activity of the renin-angiotensin-aldosterone
system, enhanced sympathetic activity and reduced
endothelium-dependent vasodilation. Particular focus
should be lent to patterns of elevated blood pressure
that have been found to be more prevalent in this
population and to increase the risk of target organ
damage, including elevated nighttime BP and the
presence of non-dipping.
Lifestyle changes, including weight loss; regular
exercise; ingestion of a high-fibre, low-fat, low-salt
diet; and moderation of alcohol intake should be
encouraged where appropriate. Potentially interfering
substances should be withdrawn or down-titrated as
clinically allowable.
Maximise Adherence
Treatment adherence worsens with the use of an
increasing number of pills, with increasing complexity
of the dosing regimen, and as out-of-pocket costs
increase. Accordingly, prescribed regimens should
be simplified as much as possible, including the use
of a long-acting combination of products to reduce
the number of prescribed pills and to allow for oncedaily dosing. Adherence is also enhanced by more
frequent clinic visits and by having patients record
home blood pressure measurements. Involving the
patient by having him or her maintain a diary of home
blood pressure values should improve follow-up and
enhance medication adherence, while involvement of
family members will likely enhance persistence with
recommended lifestyle changes.
Night time dosing
A recent cross-sectional analysis of ambulatory
blood pressure control indicated that patients taking
at least one of their hypertensive agents at bedtime
had better 24-hour mean blood pressure control and,
in particular, lower nighttime systolic and diastolic
blood pressure values. 21
Salt restriction (ndT)
Salt restriction has been shown to lower blood
pressure in patients with and without hypertension.
In the Dietary Approaches to Stop Hypertension
(DASH)-Sodium trial, sodium reduction from 100 to
50 mmol per day generally had twice the effect on
blood pressure as reduction from 150 to 100 mmol
per day]. The effect of dietary sodium restriction on
the degree of BP reduction appears to be particularly
21
robust in patients with resistant hypertension. In a
small, randomised crossover trial of patients with
resistant hypertension, a low (50 mmol/day) compared
with high (250 mmol/day) sodium diet decreased
mean office systolic BP (SBP) by 22.7 mm Hg and led
to significant reductions in daytime, nighttime and
24-h ambulatory blood pressure. 22
Thus, patients with resistant hypertension, as well
as those with CKD, demonstrate particularly saltsensitive hypertension. Patients with CKD have an
impaired ability to effectively excrete sodium and will
respond to a sodium load by raising blood pressure
in order to re-establish salt balance; this ‘pressure
natriuresis’ comes at the expense of hypertensionrelated target organ damage. In addition, dietary
sodium intake has been shown to interact with the
RAAS, particularly aldosterone, in both animal
models and human studies, to mediate hypertension,
vascular and tissue damage and kidney disease.
In a study of patients with resistant hypertension
and high 24-h urinary aldosterone, urinary protein
excretion increased significantly with progressively
greater salt intake, suggesting that aldosterone excess
and high dietary sodium intake interact to increase
proteinuria. Indeed, in a randomised, double-blind,
placebo-controlled crossover study in proteinuric
patients without diabetes, salt restriction itself exerted
an antihypertensive and antiproteinuric effect and
further enhanced the antiproteinuric effects of RAAS
blockade to nearly the same magnitude as, and in an
additive manner with, diuretics.
Diuretics
The salt-excreting handicap of CKD and resulting
extracellular volume expansion also provides the basis
for treating hypertensive CKD patients with diuretics.
Studies of resistant hypertension suggest that, even in
the absence of CKD, this group of patients manifest
increased extracellular volume, as measured by braintype natriuretic peptide (BNP) and atrial natriuretic
peptide (ANP). Therefore, use of appropriate diuretics
is a cornerstone of therapy in patients with CKD and
resistant hypertension. 10,14 Nonetheless, diuretics
remain underutilised and underdosed, and a change
in diuretic therapy may help a significant proportion
of patients with resistant hypertension achieve BP
goals. For example, while the major trials supporting
the use of diuretic therapy used chlorthalidone at 25
mg/day, the weaker hydrochlorothiazide (HCTZ) at
doses of 12.5–25 mg/day remains the most commonly
prescribed antihypertensive medication worldwide.
However, when evaluated with 24-h ambulatory BP
monitoring, the antihypertensive efficacy of HCTZ at
doses of 12.5–25 mg/day has been shown to be inferior
to that of other commonly prescribed drug classes. 45
Chlorthalidone is approximately twice as potent as
HCTZ with a much longer duration of action (8–15 h
for HCTZ compared with > 40 h for chlorthalidone).
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supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
In clinical studies using 24-h ABPM, chlorthalidone
25 mg/day results in greater reductions in 24-h mean
SBP compared with HCTZ 50 mg/day, primarily
due to its effect on reducing nighttime mean SBP. 23
Therefore, strong consideration should be given to
using chlorthalidone over HCTZ, especially given
the growing importance of nocturnal blood pressure
on cardiovascular outcomes and kidney disease
progression in patients with CKD.
Thiazide diuretics are most effective in patients with
a GFR > 50 mL/min/1.73 m 2, although chlorthalidone
can be effective to a GFR of 30–40 mL/min/1.73 m 2
in the absence of severe hypoalbuminaemia. A loop
diuretic is preferred for patients with advanced CKD
(GFR < 30 ml/min). Typically, loop diuretics such
as furosemide and bumetanide should be dosed at
least twice daily given their short duration of action
and the potential for intermittent natriuresis leading
to a reactive increase in the RAAS (with ensuing
sodium retention) if dosed once daily. The longeracting torsemide can be dosed once or twice daily.
Consideration should also be given to combining the
loop diuretic with a diuretic that acts more distally
in the nephrone, such as a thiazide or a low-dose
potassium-sparing diuretic. 24
Amiloride antagonises the epithelial sodium channel
in the distal collecting duct of the kidney, thereby
functioning as an indirect aldosterone antagonist. In a
study of 38 patients with low-renin hypertension whose
blood pressure was uncontrolled with multiple drugs,
including a diuretic, substitution with the combination
of amiloride 2.5/hydrochlorothiazide 25 mg daily
for the prior diuretic lowered systolic and diastolic
blood pressure by 31 and 15 mm Hg, respectively. 1
In 26 patients, the amiloride/hydrochlorothiazide
doses were doubled with an additional reduction in
systolic and diastolic blood pressure of 11 and 4 mm
Hg, respectively.
Adequate RAAS blockade
Targeting the RAAS with angiotensin-converting
enzyme (ACE) inhibitors and angiotensin-receptor
blockers (ARBs) is a well-established therapeutic
strategy to target hypertension, slow the progression
of CKD and reduce morbidity and mortality in heart
failure. However, many patients progress despite
treatment, and clinical trials of ACE inhibitors and
ARBs suggest that after an initial decline, plasma
aldosterone levels will increase in 30–40% of patients
o ve r t h e l o n g t e r m , a p h e n o m e n o n k n o w n a s
‘aldosterone breakthrough’. Aldosterone breakthrough
has been linked to adverse outcomes such as LVH,
impaired exercise capacity, urinary albumin excretion
and a more rapid decline in GFR. 25
One therapeutic option to target incomplete
blockade of the RAAS is dual blockade with the
combination of ACE inhibitors and ARBs, which has
been shown to confer modest BP reductions of an
average of 4/3 mm Hg compared with monotherapy as
well as proteinuria reductions of 30 and 39% compared
with monotherapy with ACE inhibitors and ARBs,
respectively. However, improved cardiovascular
and renal outcomes have not been consistently
demonstrated despite these additional reductions
in BP and proteinuria. An alternative strategy is to
use ‘ultrahigh’ doses of ACE inhibitors or ARBs.
Several small, short-term clinical studies in patients
with hypertension and CKD have found significant
incremental reductions in proteinuria after treatment
with ARBs at higher than conventional doses, albeit
without additional blood pressure changes. 26
Suppressing the RAAS with mineralocorticoid
receptor blockers (MRBs), such as spironolactone
and eplerenone, has gained renewed interest as
a treatment for resistant hypertension in patients
with and without CKD. Recent studies have found
significantly higher aldosterone levels and an elevated
aldosterone to renin ratio (ARR) in over a third of
patients with resistant hypertension, despite persistent
extracellular volume expansion. In this setting, MRBs
have emerged as effective therapy for patients with
resistant hypertension, with and without CKD. The
strongest evidence for the efficacy of MRBs in resistant
hypertension comes from two studies. In 2007, the
Anglo-Scandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm (ASCOT-BPLA) showed that
fourth-line add-on therapy with spironolactone, at a
median treatment duration of 1.3 years and a starting
dose of 25 mg/day, resulted in a mean reduction in
SBP of 21.9 mm Hg (95% CI: 20.8–23.0 mm Hg) and in
diastolic BP of 9.5 mm Hg (95% CI: 9.0–10.1 mm Hg).
Subsequently, the randomised, double-blind, placebocontrolled addition of Spironolactone in Patients with
Resistant Arterial Hypertension (ASPIRANT) trial
demonstrated a mean decrease in daytime systolic
ambulatory BP of 5.4 mm Hg (P = 0.02), as well as
significant decreases in ABPM nighttime systolic (8.6
mm Hg, P = 0.01), 24-h ABPM systolic (9.8 mm Hg,
P = 0.004) and office systolic BP values (6.5 mm Hg,
P = 0.01), with spironolactone 25 mg/day at 8 weeks
of therapy. 26 These pateients need to be monitored
for hyperkalaemia. In a cohort of 46 patients with
mean eGFR 56.5 ± 16.2 mL/min/1.73 m 2 who had
spironolactone (25 mg/day) or eplerenone (50 mg/day)
added to a stable antihypertensive regimen, including
a maximally dosed RAAS blocker and an appropriately
dosed diuretic, a baseline eGFR ≤ 45 mL/min/1.73 m 2
and a baseline serum potassium > 4.5 mEq/L were
the strongest predictors of hyperkalemia (defined as
serum potassium > 5.5 mEq/L).27 With close monitoring
of potassium, the use of MRBs in patients with early
stage CKD, or with later stage CKD and a low baseline
potassium level and/or concomitant use of diuretics,
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
Confirming Resistance to Antihypertensive Therapy
In accordance with the defining criteria of hypertension and of drug resistance
Ruling out Possibilities of Pseudoresistance
Ensure patient adherence to prescribed regimen
Rule out white coat effect by BP assessment at home / workplace / ABPM
Identification and Correction of Influencing Lifestyle Factors
Ensure implementation of interventions to address obesity, lack of exercise,
smoking, alcoholism, excessive salt consumption
Control of Influencing Medication Use
Discontinue or minimize the use of NSAIDs, sympathomimetics, oral
contraceptives, steroids, etc.
Workup to Identify Secondary Causes of Hypertension
Consider possibilities of CKD, obstructive sleep apnoea, renal artery stenosis,
pheochromocytoma, Cushing’s syndrome, primary aldosteronism, etc.
Drug Therapy
Optimize diuresis (maximize diuretic therapy, consider addition of
aldosterone antagonist; use loop diuretic in advanced CKD, as appropriate);
Evaluate prescribed drug combinations; consider inclusion of drugs from
different classes, with possible synergistic efficacy and acceptable safety
Optimize dosing to maximize efficacy, and ensure smooth 24-hour control
Fig. 1 : Systematic approach to Resistant Hypertension
can be a safe and effective therapeutic strategy for
resistant hypertension.
Sympathetic nervous system (SNS)
In patients with resistant hypertension despite a
combination regimen directed at both salt/volume
excess and the RAAS, the first step would be to identify
patients in whom persistent salt/volume excess is
sustaining hypertension and who would benefit from
bolstering the diuretic regimen. While the presence
of oedema is an important clinical clue, patients with
both resistant hypertension and CKD may manifest
occult extracellular volume expansion. Suppressed
ambulatory PRA, interpreted in the context of existing
antihypertensive therapy, can indicate this occult
volume excess and need for more diuresis. The second
option in this algorithm is the addition of medications
directed at SNS-mediated hypertension, mainly αand β-blockers, in clinical circumstances that suggest
hypertension driven by the SNS, such as sleep apnoea.
Alpha Blockers can be useful in treating resistant
hypertension when used in combination with agents
such as diuretics, beta-blockers, and angiotensinconverting enzyme inhibitors. To be maximally
effective, they should usually be combined with a
diuretic. Since alpha-blockers can have somewhat
beneficial effects on blood glucose and lipid levels,
23
they can potentially neutralise some of the adverse
metabolic effects of diuretics. The alpha-blockers are
effective in treating benign prostatic hypertrophy, and
so can be a valuable part of hypertension treatment
regimens in older men who have this condition. 28
Combination Therapy
An abundance of studies demonstrate additive
antihypertensive benefit by combining 2 agents of
different classes. This is particularly true of thiazide
diuretics, which significantly improve blood pressure
control when used in combination with most if not
all other classes of agents. In the Veterans Affairs
Single Drug Therapy Cooperative Study, patients not
controlled (diastolic blood pressure ≥ 90 mm Hg) on
one randomly assigned antihypertensive medication
(thiazide diuretic, ACE inhibitor, β-blocker, calcium
channel blocker, α-blocker, or a centrally acting α
agonist) were then randomised to one of the other
medications. If diastolic blood pressure was still not
controlled, the first medication was added back in to
test the various 2-drug combinations: the combinations
that included a thiazide diuretic were consistently
more effective than combinations that did not include
the diuretic.
Beyond studies of 2-drug combinations, there
is little data assessing the efficacy of specific
combinations of 3 or more drugs. Accordingly,
recommendation of specific multidrug combinations is
largely empiric and/or anecdotal. Intuitively, it seems
most appropriate to continue to combine agents of
different mechanisms of action. In that regard, a triple
drug regimen of an ACE inhibitor or ARB, calcium
channel blocker, and a thiazide diuretic is effective
and generally well tolerated. This triple regimen can
be accomplished with 2 pills with use of various fixeddose combinations.
Although β-antagonists are indicated in the
setting of coronary heart disease or congestive
heart failure, combined α-β-antagonists, because
of their dual combination of action, may be more
effective antihypertensives, although head-to-head
comparisons of maximal doses are lacking. Recent
studies indicate an add-on antihypertensive benefit
of aldosterone antagonists in patients uncontrolled
on multidrug regimens. Centrally acting agents are
effective antihypertensive agents but have a higher
incidence of adverse effects and lack outcome data.
Lastly, potent vasodilators such as hydralazine
or minoxidil can be very effective, particularly at
higher doses, but adverse effects are common. With
minoxidil especially, reflexive increases in heart rate
and fluid retention occur such that concomitant use of
a β-blocker and a loop diuretic is generally necessary.
Ultimately, combinations of 3 or more drugs
must be tailored on an individual basis taking into
consideration prior benefit, history of adverse events,
24
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
contributing factors, including concomitant disease
processes such as CKD or diabetes, and patient
financial limitations. Treatment recommendations in
this setting cannot be overly standardised, particularly
when going beyond 3 drugs.
Newer drug therapy
The antagonism of endothelin receptor is a newer
approach for the treatment of hypertension using
antihypertensive medications which is currently
under evaluation. Among the several endothelin
r e c e p t o r a n t a g o n i s t , d a r u s e n t a n i s a s e l e c t i ve
antagonist for type A endothelin receptors which
causes vasoconstriction and proliferation of vascular
smooth muscle]. But findings from other study
failed to meet its beneficial effect on blood pressure
reduction and the drug’s future remains uncertain.
Atrasentan, another highly selective endothelin
receptor antagonist exhibited blood pressure reduction
while study conducted on 72 patients. Another
interesting approach for the management of resistant
hypertension is administration of nitric oxide donors.
Small clinical study conducted on 6 patients with
resistant hypertension reveals that the combination of
nitrates with phosphodiesterase-5 inhibitors resulted
in significant blood pressure reduction (Figure 1). 29
Interventional management of resistant hypertension
Renal denervation
Efferent sympathetic outflow to the kidney
stimulates renin release, increases tubular sodium
reabsorption, and reduces renal blood flow;
afferent signals from the kidney modulate central
sympatheticoutflow and contribute to neurogenic
hypertension. 17 Based on the evidence of the role of
renal sympathetic nerves in various aspects of blood
pressure control, a catheter based approach using
radiofrequency energy to selectively target and disrupt
the renal nerves has been developed.
Following observational safety and feasibility
studies, the Symplicity HTN-2 Trial, a multicentre,
prospective randomised trial, 18 was performed in
patients who had a baseline systolic blood pressure
> 160 mm Hg (> 150 mm Hg for patients with type 2
diabetes) despite taking three or more antihypertensive
drugs. There were no serious procedure related
or device related complications and occurrence of
adverse events did not differ between groups. There
were no adverse effects on the kidney, and this was
also the case for patients with impaired renal function
In summary, the available evidence indicates that
catheter based renal denervation has a favourable
safety profile and results in potentially substantial and
sustained blood pressure reduction in patients with
drug resistant hypertension. In pilot studies, no loss of
antihypertensive response was evident with follow-up
of 2 years. Effects on cardiovascular morbidity and
mortality are currently unknown.
Carotid baroreflex activation
Another device based therapy of resistant
hypertension is carotid baroreflex activation, in
which stimulating electrodes are implanted in the
perivascular space around the carotid sinuses. The
Rheos Baroreflex Hypertension Therapy System
enhances afferent nerve traffic from the baroreceptors
to the cardiovascular control centres of the brain, which
subsequently reduce sympathetic outflow and blood
pressure. Initial results justify further development
and investigation of baroreflex activation therapy. 30
Prognosis
The prognosis of patients with resistant hypertension
compared 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 commonly
have associated cardiovascular risk factors such as
diabetes, obstructive sleep apnoea, left ventricular
hypertrophy (LVH), and/or CKD. The degree to
which cardiovascular risk is reduced with treatment
of resistant hypertension is unknown. 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). 31 How much of this
benefit occurs with successful treatment of resistant
hypertension is unknown.
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