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14.7.2012
Nephrol Dial Transplant (2012) 27: 4041–4045
doi: 10.1093/ndt/gfs384
Advance Access publication 16 August 2012
Resistant hypertension and the neglected antihypertensive: sodium
restriction
Rajiv Agarwal
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
Correspondence and offprint requests to: Rajiv Agarwal; E-mail: [email protected]
Abstract
Resistant hypertension is defined as blood pressure (BP)
that remains above goal (such as 140/90 mmHg or more)
in spite of the concurrent use of three antihypertensive
agents of different classes. Ideally, one of the three agents
should be a diuretic and all agents should be prescribed at
optimal dose amounts. Prevalent among 15% of the
treated hypertensives, the risk factors for resistant hypertension include older age, chronic kidney disease (CKD),
obesity and diabetes mellitus. Causes of resistant hypertension can be classified into four groups: poor adherence,
biological–behavioral factors, CKD and secondary
causes, and drugs or exogenous substances. However,
before labeling the diagnosis of resistant hypertension, it
is important to exclude pseudo-resistant hypertension
using home BP monitoring in most patients and ambulatory BP monitoring in a few. Before thinking about the
next antihypertensive drug, it is important to restrict
dietary sodium. Educating the patient on how to interpret
the food label and providing feedback by assessing
sodium intake with 24 h urine collection are effective
sodium restriction strategies. Sodium restriction can lower
BP and among patients with proteinuria can even enhance
the anti-proteinuric effects of drugs that block the renin–
angiotensin system. Sodium restriction is therefore a valuable but a neglected antihypertensive.
Keywords: dietary intake; hypertension; resistant hypertension; sodium
Resistant hypertension: definitions and
epidemiology
According to the definition endorsed by the American
Heart Association, resistant hypertension is defined as
Published by Oxford University Press on behalf of ERA-EDTA 2012. All rights reserved.
For Permissions, please e-mail: [email protected]
4042
blood pressure (BP) that remains above goal (such as 140/
90 mmHg or more) in spite of the concurrent use of three
antihypertensive agents of different classes [1]. Ideally,
one of the three agents should be a diuretic and all agents
should be prescribed at optimal dose amounts.
Resistant hypertension is common. Among adults
treated with antihypertensive drugs in the US National
Health and Nutrition Examination Survey (NHANES)
performed between 2005 and 2008, resistant hypertension
was noted in 12.8% [2]. As a fraction of the overall hypertensive population, the prevalence of resistant hypertension was 8.9%. Thus, the number of hypertensive people
in the USA who have resistant hypertension is estimated
to be ∼6 million. As a cause of poorly controlled hypertension, therapeutic inertia may be more common than
resistant hypertension. Of the patients who were poorly
controlled, 72.4% were taking only one to three antihypertensive medications. Although the use of diuretics
among patients with uncontrolled hypertension was
85.6%, the dose may have been inadequate or the choice
of the diuretic may have been inappropriate [2].
The prevalence of resistant hypertension is increasing
[3]. Among 13 375 hypertensive adults who participated
in the NHANES, the percentage of patients who took
three antihypertensive medications or more and were
poorly controlled was 6.5% in 1988–94, 9.3% in 1999–
2004 and 13.4% in 2005–08 [3]. The percentage of hypertensive patients who were left untreated declined from
59.0% in 1988–94, 56.1% in 1999–2004 and 52.2% in
2005–08 [3]. However, the prevalence of treated patients
who took three antihypertensive medications or more and
were poorly controlled increased from 15.9% in 1988–94,
21.2% in 1999–2004 and 28.0% in 2005–08 [3]. Resistant
hypertension in the NHANES survey (2005–08) was independently associated with older age, black race, obesity,
chronic kidney disease (CKD), an elevated CHD risk
(>20% at 10 years) and frequent healthcare visits (4 or
more per year) [3].
Some estimates of the prevalence of resistant hypertension can be derived from recent trials because of the need
to force titrate drugs to achieve BP control. From these
trials that have a large number of patients with multiple
morbidities, it is estimated that 35–50% of the participants
may have resistant hypertension [4].
The incidence of resistance hypertension was evaluated
in a large retrospective study from a managed health
organization in US, Kaiser Permanente [5]. Incident hypertension was defined as elevated BP based on Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood
Pressure thresholds with lower BP thresholds for diabetes
mellitus or CKD (130/80 mmHg). After diagnosis of hypertension, patients were followed if they were ever given
at least one antihypertensive drug. Patients taking three or
more classes of antihypertensive drugs for at least 1
month were divided into two groups: controlled or uncontrolled hypertension based on their BP. Next, the study
cohort patients taking at least three medications were followed up for 1 year to assess hypertension control based
on the BP measurement closest to 1 year after they started
taking three antihypertensive medications and to assess
Nephrol Dial Transplant (2012): Editorial Review
adherence to antihypertensive medications. Among those
in whom hypertension was controlled at 1 year, those
taking four medications were considered resistant and
those taking <3 medications were considered non-resistant. Among those in whom BP was not controlled at 1
year, those taking up to three medications were considered
non-resistant and those taking three or more medications
were considered resistant.
Of the ∼200 000 patients with incident hypertension,
∼42 000 (21%) were prescribed at least three medications
which they took for at least 1 month. Further data were
available on ∼25 000 participants. At baseline, ∼25% had
BP controlled. Of those with controlled hypertension, at
the end of the year, ∼75% remained controlled. Of the
remaining 25% with poor control, only ∼25% were resistant. The vast majority were not treated adequately (therapeutic inertia) and a small fraction (<4%) were nonadherent. At baseline, poor control of BP was present in
75%. Of these, 55% had BP well controlled at 1 year.
Since 7% of the latter needed at least four medications,
they had resistant hypertension. Forty-five percent had
poor control of BP at 1 year. Of the latter, the distribution
of hypertension was as follows: resistant hypertension
was present in 38%, non-adherence in 5% and therapeutic
inertia in 56%. Overall, the annual incidence of resistant
hypertension was 1.9% of the incident hypertensive population. Since 3801 patients of the initial 24 499 patients
who required at least three antihypertensive drugs at
baseline had resistant hypertension, the incidence of
resistant hypertension in this more meaningful group was
15.5%.
One has to reconcile the low overall incidence of resistant hypertension (<2%) with overall prevalence of 12.8%
by one estimate [2], 15.5% in another [5] and 28.0% [3]
in a third study. Furthermore, the prevalence of resistant
hypertension has increased 1.8-fold over two decades [3].
Since the number of untreated patients has declined [3],
the intensity of treatment has likely increased over the
same period. By definition, increased use of antihypertensive therapy would increase the prevalence of resistant hypertension. Although resistant hypertension is deemed to
increase cardiovascular risk [5], current data suggest that
this risk is largely driven by incident CKD. Better care of
CKD and increased survival of these patients may elicit
an increase in the prevalence of resistant hypertension.
Resistant hypertension has many causes. Truly resistant
hypertension can be classified into four major categories
(Table 1): non-adherence to therapy; biological and behavioral factors (examples of which include older age,
excess sodium intake, obesity and smoking); CKD and
other secondary causes of hypertension (such as aldosteronism, diabetes mellitus and sleep apnea) and drugs
either prescribed (cyclosporine, erythropoietin, NSAIDs)
or recreational (for example cocaine). Although some
regard non-adherence as pseudo-resistant hypertension,
adherence is difficult to assess by medication possession
[5]; accordingly, non-adherence should be considered as a
cause of resistant hypertension. Nonetheless, before we
label the diagnosis of resistant hypertension, it is important to exclude pseudo-resistant hypertension. It should be
noted that despite being pseudo-resistant, these patients
Nephrol Dial Transplant (2012): Editorial Review
Table 1. Causes of resistant hypertension (ABCD)
A. Non-adherence to therapy
B. Biological and behavioral factors
Older age
Excess sodium intake
Low potassium intake
Obesity
Smoking
C. Chronic kidney disease and other secondary causes of hypertension
Aldosteronism
Diabetes mellitus
Sleep apnea
D. Drugs
Prescribed (e.g. cyclosporine, erythropoietin, NSAIDs)
Recreational (e.g. cocaine)
Pseudo-resistant hypertension.
likely have cardiovascular risk that is many times that of
true normotensives.
Pseudo-resistant hypertension is diagnosed by above
threshold BP in the clinic but at goal BP outside the clinic.
Although the gold standard for out-of-clinic BP monitoring is by ambulatory BP recording, home BP can serve as
an effective way to screen those who may need ambulatory
BP monitoring [6]. Home BP of 136/86 mmHg is considered hypertensive. If home BP is <125/75 mmHg, then
patient may be considered a true normotensive and no
ambulatory BP monitoring is needed. If BP is >135/85,
then true hypertension is diagnosed. However, the gray
zone between 125–135 and 75–85 mmHg requires further
evaluation with ambulatory BP monitoring [6]. It is in
these patients that ambulatory BP can discriminate
between hypertensive and normotensive better than home
BP monitoring.
A large Spanish registry of ambulatory BP recording
evaluated 68 045 patients and found that 8295 (12%) of
these patients taking three drugs or more had clinic BP of
140/90 mmHg or more [7]. Thus, these patients in the
absence of further BP recordings would be labeled as
resistant hypertensives. However, when these patients underwent ambulatory BP monitoring, it was found that
37.5% of these people had pseudo-resistant hypertension
[7]. In other words, they simply had white coat effect.
Thus, one in three patients will be wrongly classified as
resistant hypertension in the absence of out-of-clinic BP
monitoring. Given that office BP has no prognostic value
but ambulatory BP is a strong predictor of cardiovascular
morbidity and mortality in resistant hypertension [8], this
finding is important for treating physicians and trialists
alike. True resistant hypertension is more likely to respond
to therapy than pseudo-resistant hypertension.
Dietary sodium intake and its role in resistant
hypertension
Increased dietary sodium intake in modern societies is an
important and treatable cause of hypertension. A metaanalysis combining results of 50 studies shows that
78 mmol/day (1.8 g) reduction in dietary sodium is associated with a reduction in BP among hypertensive people of
4043
5.0/2.7 mmHg [9]; among non-hypertensives, BP is reduced
by 2.0/1.0 mmHg [9]. Among children, a similar metaanalysis suggests lowering of BP by 1.2/1.3 mmHg [10].
In the Dietary Approaches to Stop Hypertension
(DASH) randomized controlled trial, the sodium intakes in
the three levels of dietary sodium prescriptions led to
intakes of sodium of ∼150, 100 and 65 mEq/day [11].
Compared with the highest sodium intake, BP was reduced
2.1 mmHg systolic with moderate (100 mEq/day) sodium
restriction. Compared with the highest sodium intake, BP
was reduced 6.7 mmHg systolic with greater (65 mEq/day)
sodium restriction. The greatest reductions in BP were seen
among blacks, women and those with hypertension.
To lower the incidence of hypertension, the Institute of
Medicine now recommends that dietary sodium should be
restricted to <1500 mg/day (65 mmol/day) [12]. However,
the intake of sodium between 1988 and 1994 was 2900–
4300 mg/day or two to three times recommended. More
recent estimates (2005–06) suggest that the average man
in the USA consumed 4 g sodium; the average woman
2.8 g/day [13]. Statistical simulations suggest that reducing dietary sodium intake by 1200 mg/day can lead to
substantial reduction in coronary heart disease, stroke,
myocardial infarction and all-cause mortality [13]. These
reductions would be more cost-effective than treating with
antihypertensive drugs [13]. Dietary sodium restriction is
also recommended as an initial step to treat pre-hypertension and Stage I hypertension. Data are now emerging
that even people with later stage hypertension including
those being treated with multiple antihypertensive agents
such as those with resistant hypertension can benefit with
this strategy.
Since most sodium intake comes from processed food,
and only ∼10% from table salt, it is important to educate
the patient to read food label. Even the fast food restaurants can provide information about the sodium content of
their food and often have low-sodium options. To assess
adherence to low-sodium diet, requires the collection of
24-h urine for sodium and creatinine. In an adequately collected sample, dietary sodium excretion of >65 mmol/day
suggests >1500 mg sodium intake/day. Better response to
the existing antihypertensive drugs can be expected if such
patients lowered their dietary sodium intake.
Only a few studies are available that have restricted
sodium intake among patients with resistant hypertension.
Pimenta et al. [14] performed a randomized cross-over
trial of dietary salt restriction on office and 24-h ambulatory BP in subjects with resistant hypertension. Twelve
subjects with resistant hypertension were given a low- (50
mmol/24 h × 7 days) and high-sodium diets (250 mmol/
24 h × 7 days) separated by a 2-week washout period. At
baseline, subjects were on an average of 3.4 antihypertensive medications with a mean office BP of 145.8 ± 10.8
systolic and 83.9 ± 11.2 mm Hg diastolic. The mean
urinary sodium excretion were ∼50 mmol versus 250
mmol/24 h during low- versus high-salt intake. Low- compared with high-salt diet decreased office systolic and diastolic BP by 22.7 and 9.1 mm Hg, respectively. The
reduction in ambulatory BP was similar (20.1/9.8 mmHg).
Plasma renin activity increased whereas brain natriuretic
peptide and creatinine clearance decreased during low-salt
4044
intake, indicative of intravascular volume reduction. Other
trials have not predefined a population of resistant hypertension, but it is likely that quite a large percent had resistant hypertension and will be considered further.
Fotherby and Potter [15] performed a double-blind,
randomized, placebo-controlled, crossover trial lasting 10
weeks, following a 4-week run-in period to assess the
effects of 80 mmol/day reduction in dietary sodium intake
on clinic and 24-h ambulatory BP in elderly hypertensive
subjects. Seventeen untreated older [mean age 73 years
(range 66–79)] subjects with essential hypertension [systolic BP (SBP) 160 mmHg or more and/or diastolic BP
(DBP) 95 mmHg or more] had clinic BP and 24-h urinary
electrolyte excretion measured while on their normal diet.
Following a 4-week run-in period on a reduced sodium
diet (80–100 mmol/24 h), subjects entered a 10-week
crossover trial of 80 mmol/24 h sodium supplement or
matching placebo while continuing on the reduced
sodium diet. The mean office BP was 176/96 mmHg.
There was a significant reduction in clinic supine SBP
between the high- and low-sodium phases. There was a
non-significant reduction (5/2 mmHg) in the mean 24-h
SBP and DBP on the low-sodium intake. Overall, moderate sodium restriction in elderly hypertensives resulted in
a significant fall in clinic supine SBP only, although
marked differences in intersubject responses were found.
Gavras et al. [16] reported an uncontrolled trial of
dietary sodium restriction (10 mmol/day × 6–14 day) and
diuretics [furosemide 80–200 mg/day if CKD (n = 2) or
HCTZ 100 mg] among patients with uncontrolled hypertension in maximum doses of two agents (a diuretic plus
a sympatholytic). If renin–angiotensin system was not activated, spironolactone 100–300 mg was given for 4–16
days. The office BP was 176/116 mmHg at baseline, so it
is quite likely that most patients had resistant hypertension. After treatment, BP fell to 155/109 mmHg (change
of 21/7 mmHg from baseline). Patients with the least
percent increase in PRA demonstrated the greatest fall in
BP per unit of weight loss, indicating that relative activation of the renin–angiotensin system may be the factor
limiting antihypertensive efficacy of sodium depletion.
However, with the wide availability of renin–angiotensin
aldosterone system blockers, resistance to BP-lowering
effect with sodium depletion is no longer insurmountable.
CKD is a risk factor for resistant hypertension. The
pharmacological effects of renin–angiotensin system
blockers are enhanced when they are used along with
sodium restriction. When sodium is restricted, not only is
the BP reduced further, an improvement in proteinuria is
also seen [17, 18].
Dialysis patients have a high prevalence of resistant hypertension. In a survey of 369 dialysis patients who had
ambulatory BP recorded, four or more antihypertensive
drugs were used by 59 (16%) of the patients [19]. Thus,
these patients had resistant hypertension by current definition. Another 57 (15%) had three drugs being used for
hypertension and the odds ratio for poor control with
three drugs was 2.49 (P = 0.03). Accordingly, ∼25% of
the patients on dialysis may have resistant hypertension.
Sodium restriction both dietary and in the dialysate are
the cornerstones for treating resistant hypertension [20].
Nephrol Dial Transplant (2012): Editorial Review
More importantly, volume reduction through ultrafiltration
in patients consuming recommended intake of sodium is
an effective way to lower BP. Since these patients are
treated with multiple drugs, this is an effective strategy of
controlling resistant hypertension. The volume control
strategy has been tested in one randomized controlled trial
[21]. The Dry-weight Reduction In Hypertensive Hemodialysis Patients (DRIP) trial randomized 150 patients in
2:1 ratio to either aggressive volume reduction or a
control group [21]. Within 4 weeks, BP reduction assessed by interdialytic ambulatory BP monitoring of ∼7/
3 mmHg was achieved. Despite the intake of an average
of 2.5 antihypertensive drugs, this reduction in BP
suggests that in this difficult to treat group, volume
control was effective in providing additional antihypertensive effect. A recent analysis of the Hemodialysis
(HEMO) study found an independent association of
dietary sodium intake with all-cause mortality [22].
Animal studies show that dietary sodium restriction can
evoke better vascular structure and function, regression of
left ventricular hypertrophy and improvement in vascular
inflammation and fibrosis [23–25]. Thus, dietary sodium
restriction might have effects beyond BP reduction and
extend to cardiovascular protection.
It is important to note that the BP-raising effects of
sodium may be modulated by potassium. The mechanisms of these effects are discussed in a scholarly review
by Adrogue and Madias [26]. For example, in the DASH
study, despite a high-sodium intake, when the diet was
rich in fruits and vegetables (and therefore dietary potassium), a lower BP was seen, despite a higher sodium
intake [11]. Likewise, a meta-analysis pointed out the
benefits of potassium intake in lowering BP but pointed
out the great heterogeneity between studies [27]. In fact,
some studies point out that it is the Na/K ratio in the urine
that associates with increased risk for cardiovascular
events [28]. Although it has been suggested that restriction in sodium intake that is accompanied by increased
intake of potassium can profoundly improve the prevalence of hypertension and cardiovascular disease [29], the
safety and efficacy of this recommendation among
patients with CKD will need prospective trials.
Conclusions
Resistant hypertension is seen among 15% of the treated
hypertensives. Risk factors for resistant hypertension
include older age, CKD, obesity and diabetes mellitus.
The four broad causes of resistant hypertension can be remembered with the mnemonic ABCD (adherence, biological–behavioral, CKD-secondary, drugs). However,
before labeling the diagnosis of resistant hypertension, it
is important to exclude pseudo-resistant hypertension
using home BP monitoring in most patients and ambulatory BP monitoring in a few. Before thinking about the
next antihypertensive drug, it is important to consider
dietary sodium restriction. Educating the patient on how
to interpret the food label and providing feedback by assessing sodium intake with 24 h urine collection are effective ways to implement sodium restriction. Sodium
Nephrol Dial Transplant (2012): Editorial Review
restriction can lower BP and among patients with proteinuria can even enhance the antiproteinuric effects of
drugs that block the renin–angiotensin system. Accordingly, dietary sodium restriction is a potent—but forgotten
—antihypertensive agent.
Acknowledgements. This study was funded by NIH 2R01-DK062030-08.
Conflict of interest statement. R.A. serves on the speakers’ bureau of
Merck and has served as a consultant for Dachii Sankyo and Takeda. All
these companies manufacture and marked medications to treat
hypertension.
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Received for publication: 1.6.2012; Accepted in revised form: 13.7.2012