Download Resistant Hypertension

Journal of the American College of Cardiology
© 2008 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 52, No. 22, 2008
ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2008.08.036
STATE-OF-THE-ART PAPER
Resistant Hypertension
An Overview of Evaluation and Treatment
Pantelis A. Sarafidis, MD, PHD,* George L. Bakris, MD, FAHA, FASN†
Thessaloniki, Greece; and Chicago, Illinois
Resistant hypertension is defined as failure to achieve goal blood pressure (BP) when a patient adheres to the
maximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of resistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggests
that it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase,
owing to the aging population and increasing trends in obesity, sleep apnea, and chronic kidney disease. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis
and exclude factors associated with “pseudo-resistance,” such as improper BP measurement technique, the
white-coat effect, and poor patient adherence to life-style and/or antihypertensive medications. Education and
reinforcement of life-style issues that affect BP, such as sodium restriction, reduction of alcohol intake, and
weight loss if obese, are critical in treating resistant hypertension. Exclusion of preparations that contribute to
true BP treatment resistance, such as nonsteroidal anti-inflammatory agents, cold preparations, and certain
herbs, is also important. Lastly, BP control can only be achieved if an antihypertensive treatment regimen is
used that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to overcome treatment resistance in this instance. (J Am Coll Cardiol 2008;52:1749–57) © 2008 by the American
College of Cardiology Foundation
Hypertension is the most common chronic disease in
developed societies, affecting ⬎25% of adults (1). Metaanalyses have demonstrated a linear relationship between
level of blood pressure (BP) and risk for cardiovascular
events (2– 4). Suboptimal BP control is, consequently, the
most common attributable risk for death worldwide, being
responsible for 62% of cerebrovascular disease and 49% of
ischemic heart disease as well as an estimated 7.1 million
deaths a year (5).
In the U.S., both the net and age-adjusted prevalence
ratios of hypertension continue to increase. Recent data
suggest, however, a slight improvement in hypertension
awareness, treatment, and control (6). The rates of hypertension treatment and control in Europe are much lower
than in the U.S. (7). Several large hypertension outcome
trials also demonstrate a failure to achieve BP goals in spite
of protocol-defined treatment regimens. In these trials, 20%
to 35% of participants could not achieve BP control despite
receiving ⬎3 antihypertensive medications (8 –10) (Fig. 1).
From the *Section of Nephrology and Hypertension, 1st Department of Medicine,
AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; and
the †Hypertensive Diseases Unit, Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago Pritzker School of Medicine,
Chicago, Illinois.
Manuscript received June 20, 2008; revised manuscript received August 18, 2008,
accepted August 26, 2008.
This article provides the clinician with an overview of the
patient characteristics associated with resistant hypertension, the diagnostic evaluation to assess the problem, and
the treatment strategies for optimizing BP control.
Definition and Prevalence
of Resistant Hypertension
The Joint National Committee 7 defines resistant hypertension as failure to achieve goal BP (⬍140/90 mm Hg for
the overall population and ⬍130/80 mm Hg for those with
diabetes mellitus or chronic kidney disease) when a patient
adheres to maximum tolerated doses of 3 antihypertensive
drugs including a diuretic (11). This definition does not
apply to patients who have been recently diagnosed with
hypertension (12). Moreover, resistant hypertension is not
synonymous with uncontrolled hypertension. The latter
includes all hypertensive patients who lack BP control under
treatment, namely, those receiving an inadequate treatment
regimen, those with poor adherence, and those with undetected secondary hypertension, as well as those with true
treatment resistance. By this definition, patients with resistant hypertension may achieve BP control with full doses of
4 or more antihypertensive medications (13,14). Although
the definition of resistant hypertension is arbitrary relative
to the number of antihypertensive medications required, the
concept of resistant hypertension is focused on identifying
1750
Sarafidis and Bakris
Resistant Hypertension
patients who are at high risk of
having reversible causes of hypertension and/or patients who, beACE ⴝ angiotensincause of persistently high BP levconverting enzyme
els, may benefit from special
ARB ⴝ angiotensindiagnostic or therapeutic considreceptor blocker
erations (13).
BP ⴝ blood pressure
The prevalence of resistant hyCCB ⴝ calcium-channel
pertension in the general popublocker
lation is unknown because of an
eGFR ⴝ estimated
inadequate sample size of pubglomerular filtration rate
lished studies as well as the feaERA ⴝ endothelin-receptor
sibility of doing a large enough
antagonist
prospective study that would anNSAID ⴝ nonsteroidal antiinflammatory drug
swer the question (15,16). Small
studies, however, demonstrate a
RAS ⴝ renin-angiotensin
system
prevalence of resistant hypertension that ranges from ⬇5% in
general medical practice to
⬎50% in nephrology clinics (15).
Based on data from the National Health And Nutrition
Examination Survey, 2003 to 2004, 58% of people being
treated for hypertension achieve BP levels ⬍140/90 mm Hg
(6); control rates among those with diabetes mellitus or
chronic kidney disease are ⬍40% (6,17). In Europe, the
situation is worse, with control rates among treated hypertensive patients between 19% and 40% in 5 large countries
(7). Such data suggest that resistant hypertension is more
common than appreciated; however, accurate estimates are
Abbreviations
and Acronyms
Figure 1
Percent of Patients Reaching JNC-7 BP Goals
Percent of patients reaching the Joint National Committee 7 (JNC-7) blood
pressure (BP) goals in the following trials: ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension): amlodipine plus benazepril versus benazepril plus hydrochlorothiazide
(56); INVEST (International Verapamil-Trandolapril Study): verapamil versus
atenolol (10); CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points): verapamil versus atenolol (57); ALLHAT (Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial): chlorthalidone versus lisinopril versus amlodipine (8); and LIFE (Losartan Intervention For Endpoint Reduction in Hypertension Study): losartan versus atenolol (9). Note that,
in all of these trials, more than two-thirds of the patients were receiving at
least 2 antihypertensive agents and about one-third were receiving 3 or more
antihypertensive agents.
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
not possible, as control rates under treatment are affected by
many factors.
Prognosis of Resistant Hypertension
There are no studies specifically powered to address the
prognosis of persons with resistant hypertension. However,
as evident from all population studies on hypertensionrelated target-organ damage, the risks of myocardial infarction, stroke, heart failure, and renal failure directly relate to
the level of BP (3,11).
These observations coupled with the most common
comorbid conditions seen in patients with resistant hypertension, namely, obesity, diabetes, or chronic kidney disease,
translate into an unfavorable prognosis if the BP goal is not
achieved (13). The extent of cardiovascular morbidity and
mortality reduction with achievement of the BP goal has not
been evaluated; however, the benefits are evident by results
of major outcome studies (2,11,18,19).
Etiology of “Pseudo-Resistance”
The term “pseudo-resistance” refers to lack of BP control
with appropriate treatment in a patient who does not have
resistant hypertension. Several factors contribute to elevated
BP readings and produce the perception of resistant hypertension (12–16) (Table 1). Such factors include the following: 1) suboptimal BP measurement technique; 2) the
white-coat effect; and 3) poor adherence to prescribed
therapy and other causes described in the following text
(13,14). A careful evaluation to exclude these factors before
labeling someone as having resistant hypertension should be
performed.
Although guidelines to properly assess office BP are
widely available (20), several common mistakes often produce falsely elevated BP readings. Such mistakes include not
allowing the patient to sit quietly for adequate time, taking
single instead of triple readings, using cuffs that are too
small for the arm, recent smoking, and not fully supporting
the arm at heart level (12,13,16). In older patients, the
presence of heavily calcified or arteriosclerotic arteries that
cannot be fully compressed is common and results in
overestimation of intra-arterial BP (12,16).
The “white-coat effect,” defined as an elevation of BP
during a clinic visit resulting in higher office readings than
at home or ambulatory BP readings (21), is another cause of
pseudo-resistance. The white-coat effect is common among
patients with perceived resistant hypertension; ⬇25% of
such patients referred for resistant hypertension achieve goal
BP under treatment when ambulatory measurements are
performed (22). Patients with apparent resistant hypertension due to the white-coat effect have less target-organ
damage compared with truly resistant hypertensive patients
(23,24). Therefore, such patients should have home or
ambulatory BP measurements (12).
Poor adherence to an adequate antihypertensive regimen
is another cause of apparent resistant hypertension. Studies
Sarafidis and Bakris
Resistant Hypertension
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
Causes of Pseudo-Resistant Hypertension
Table 1
Causes of Pseudo-Resistant Hypertension
Improper blood pressure measurement
Heavily calcified or arteriosclerotic arteries that are difficult to compress (in
elderly persons)
White-coat effect
Poor patient adherence
Side effects of medication
1751
inertia may be due to lack of training and experience in the
proper use of antihypertensive agents or an overestimation
of care already provided (33). Several studies (34,35) suggest
that this phenomenon is frequent among American physicians and represents an important culprit working against
the efforts to improve hypertension control rates in the
population.
Complicated dosing schedules
Poor relations between doctor and patient
Inadequate patient education
Identification and Reversal
of Pseudo-Resistance Causes
Memory or psychiatric problems
Costs of medication
Related to antihypertensive medication
Inadequate doses
Inappropriate combinations
Physician inertia (failure to change or increase dose regimens when not at goal)
suggest that up to 40% of newly diagnosed hypertensive
patients will discontinue their antihypertensive medications
during the first year, with only 40% of the remaining
patients continuing their therapy over the next decade
(25–27). An evaluation of 4,783 hypertensive patients enrolled in phase IV clinical studies, with follow-up ranging
from 30 to 330 days, demonstrated a discontinuation rate of
antihypertensive drug of ⬇50% within 1 year (28). Moreover, there was an inverse relationship between the likelihood of early treatment discontinuation and the frequency
of the daily dosing regimen. Factors that improve medication adherence include the following: 1) selection of agents
with low side effect profiles such as blockers of the reninangiotensin system (RAS); 2) avoidance of complicated
dosing schedules so that once-daily agents either alone or in
fixed dose would be preferred; 3) use of pill boxes or family
to help patients with memory deficits or psychiatric disorders; and 4) improved communication between the patient
and physician to ensure that the patient understands the
regimen and why the medication should be taken in the way
prescribed. Failing to educate the patient about the importance of achieving BP goals, the predicted side effects of the
agents, and the cost of medication are the most common
reasons for drug discontinuation (29,30).
A relatively surprising cause of pseudo-resistant hypertension is suboptimal dosing of antihypertensive agents or
inappropriate combinations of agents. Data from a clinical
hypertension specialty clinic demonstrated that either increasing the dose or initiating or switching to the proper
diuretic was the most common change that achieved BP
goal among patient referred for resistant hypertension (31).
An important culprit that contributes to the genesis of
pseudo-resistant hypertension is clinical inertia, defined as
the conscious decision by a clinician to not adequately treat
a condition despite knowing that it is present (32). Despite
efforts to translate evidence-based guidelines into clear
recommendations for clinical practice (11), many physicians
are reluctant to adhere to these guidelines (16). Clinical
Reasonable algorithms to identify people with pseudoresistant hypertension have been proposed (12,13). In general, these approaches adopt a 2-step approach: first, confirmation of true resistance (by simultaneous recognition
and correction of factors related to pseudo-resistance); and
second, identification of the factors that contribute to
treatment resistance in a given patient (Table 2).
The first step to rule out resistant hypertension is confirmation of the diagnosis with reliable office BP readings; the
observer should strictly follow the relevant BP measurement
guidelines (20). Particular attention should be paid to the
patient’s posture, environment, and triple BP readings with
adequate intervals between. Additionally, use of appropriate
cuffs and devices is mandatory. Adherence to the recomFactors Contributing to Resistant Hypertension
Table 2
Factors Contributing to Resistant Hypertension
Drug-induced
Nonsteroidal anti-inflammatory drugs (including cyclo-oxygenase-2 inhibitors)
Sympathomimetics (decongestants, anorectics)
Cocaine, amphetamines, other illicit drugs
Oral contraceptive hormones
Adrenal steroid hormones
Erythropoietin
Cyclosporine and tacrolimus
Licorice (included in some chewing tobacco)
Over-the-counter dietary and herbal supplements (e.g., ginseng, yohimbine,
ma huang, bitter orange)
Excess alcohol intake
Volume overload
Excess sodium intake
Volume retention from kidney disease
Inadequate diuretic therapy
Associated conditions
Obesity
Diabetes mellitus
Older age
Identifiable causes of hypertension
Renal parenchymal disease
Renovascular disease
Primary aldosteronism
Obstructive sleep apnea
Pheochromocytoma
Cushing’s syndrome
Thyroid diseases
Aortic coarctation
Intracranial tumors
1752
Sarafidis and Bakris
Resistant Hypertension
mended BP measurement technique will uncover patients
who do not meet the definition of resistant hypertension.
Identification of patients who have the white-coat effect
is also important. Either having qualified nonphysician
personnel (i.e., nurses) perform office measurements or
using an automated device with the patient alone in the
room is useful. Of greater importance, however, is the
determination of BP levels under treatment with home or
ambulatory measurements, again following relevant recommendations (20,36). If BP remains elevated after this
evaluation, patient adherence to therapy should be evaluated, as noted earlier.
Factors Contributing to Resistant Hypertension
Apart from the aforementioned variables, a number of
biological or life-style factors can contribute to the development of resistant hypertension. Several classes of pharmacological agents can produce transient or persistent
increases in BP (37) (Table 3). Nonsteroidal antiinflammatory drugs (NSAIDs) are a common cause of
worsening BP control. They increase BP by an average of 5
mm Hg, in part because of inhibition of renal prostaglandin
production decreases in renal blood flow, followed by
sodium and fluid retention (38). They also interfere with
BP-lowering of all antihypertensive drug classes except
Step-by-Step
Management
Resistant
Hypertension
Physician
of Patients
Guide
Appearing
for Evaluation
to Have and
Table 3
Step-by-Step Physician Guide for Evaluation and
Management of Patients Appearing to Have
Resistant Hypertension
A. Become familiar with and adhere to the most recent hypertension guidelines.
B. Identify and reverse “pseudo-resistance.”
1. Perform proper measurements of BP in the office, following the relevant
guidelines, to confirm the diagnosis of resistant hypertension.
2. Exclude the “white-coat effect” with the use of home or ambulatory BP
measurements.
3. Evaluate patient’s adherence to the treatment regimens; in case of poor
adherence, determine the causes of it. Educate the patient on the risks of
uncontrolled hypertension and the benefits of drug treatment and motivate
the patient to work toward an appropriate BP goal.
4. Closely follow-up nonadherent patients to ensure their compliance.
C. Identify and reverse factors contributing to true resistance.
1. Specifically ask the patient about use of any pharmacological agents that
may increase BP; in case of identification of such a substance, discontinue
or minimize its use.
2. Evaluate the amount of alcohol intake and counsel the patient on the
benefits of ceasing alcohol consumption.
3. Perform a reliable evaluation of dietary salt intake and recommend sodium
restriction to ⬍100 mmol (2.4 g) per day.
4. Assess the degree of obesity, abdominal obesity, and physical activity and
recommend weight reduction and regular aerobic exercise (at least 30 min/
day, most days of the week).
5. Evaluate the level of renal function with estimation of glomerular filtration
rate and modify treatment accordingly.
6. Perform a thorough search for secondary hypertension; if an identifiable cause
is present, treat accordingly or refer the patient to a hypertension center.
D. Treat aggressively with optimal doses of appropriate antihypertensive
medications (including drug combinations) according to patient
characteristics.
E. Refer the patient to a hypertension specialist if BP control is not achieved.
BP ⫽ blood pressure.
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
calcium antagonists (39,40). The effect of NSAIDs on BP is
more pronounced in patients with reduced kidney function
(13). Selective cyclo-oxygenase-2 inhibitors have effects
similar to those of NSAIDs on BP control (41). Sympathomimetic agents (nasal decongestants, anorectic pills, cocaine, amphetamine-like stimulants), oral contraceptives,
glucocorticoids, anabolic steroids, erythropoietin, and cyclosporine are also commonly used agents that can interfere
with BP control. Black licorice, included in some oral
tobacco products, and herbal supplements (e.g., ma huang
and ginseng), also raise BP (12,13,16). The effect of these
agents varies; most people manifest little or no effect, but
certain persons may experience severe BP elevations. Lastly,
illicit drugs can be a major unappreciated cause of resistant
hypertension. Agents such as steroids and cocaine are
common causes of resistant hypertension.
Although modest alcohol consumption does not generally
increase BP, larger amounts (3 or more drinks/day) have a
dose-related effect on BP, both in hypertensive and normotensive persons (11). Alcohol intake in all hypertensive
patients should be limited to no more than 1 oz of ethanol
a day in most men (the equivalent of 2 drinks) and 0.5 oz of
ethanol a day in women and lower-weight persons (11).
A key factor responsible for many cases of resistant
hypertension is excess dietary salt intake leading to volume
overload (16). Data from small studies demonstrate that
90% of patients with resistant hypertension have expanded
plasma volume (42). Excessive dietary sodium intake is
widespread in the U.S. and other developed countries, with
processed foods being the most common source (13,16).
The majority of patients with resistant hypertension have
higher salt intake than the general population, with an
average dietary sodium intake exceeding 10 g/day (43).
The optimal way to assess sodium intake is to measure
sodium excretion in a 24-h urine collection. Dietary salt
reduction to ⬍3 g/day is associated with modest BP
reductions, which are larger in African-American and elderly patients (44). Current guidelines suggest that dietary
sodium for a hypertensive person should be ⬍100 mmol/
day (2.4 g sodium or 6 g sodium chloride) (11). This
guidance is applicable to all patients with resistant hypertension, whereas for salt-sensitive patients, even lower
amounts of sodium may be necessary.
Perhaps the most common unappreciated medical cause
of resistant hypertension is the presence of renal parenchymal disease. Kidney disease is the most common secondary
medical cause of hypertension. Failure to appreciate this
relationship may lead to less than optimal choices of
antihypertensive agents such as failure to use appropriately
dosed or selected diuretics based on kidney function. This
lack of diuretic use has been shown in referral practices to be
the primary cause of resistant hypertension, with the use of
these agents helping to achieve BP goals (31).
Obesity is also a very common feature of patients with
resistant hypertension (45,46). The mechanisms by which
obesity contributes to BP elevation and interferes with BP
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
control are complex and not fully understood. Insulin
resistance and hyperinsulinemia, impaired sodium excretion, increased sympathetic nervous system activity, increases in aldosterone sensitivity related to visceral adiposity,
and obstructive sleep apnea have all been implicated as
potential causes (47– 49).
Weight loss achieved with both an appropriate exercise
program and a reduced calorie diet is associated with modest
BP reductions in obese hypertensive patients (12,13). These
reductions are greater in patients already receiving antihypertensive therapy (50).
Increasing age, namely, ⬎65 years old, is associated with
a higher prevalence of resistant hypertension (16,51). Increasing age is associated with a higher prevalence of arterial
stiffening, which is not only responsible for falsely elevated
systolic BP readings but also a major cause of true elevations
(11,16). Current guidelines for systolic BP goals of ⬍140 mm
Hg are more difficult to achieve in patients with isolated
systolic hypertension (11) and are more difficult with increasing
age because of the natural history of arteriosclerosis.
Finally, in patients with resistant hypertension, the presence
of secondary hypertension must be considered; although its
prevalence is largely unknown, previous studies have shown
that ⬇5% to 10% of patients with resistant hypertension have
an identifiable cause (52,53). As already mentioned, renal
parenchymal disease must be considered with the strict sense as
the most common medical cause of secondary hypertension
(12,16). Renal arterial disease, primary aldosteronism, and
obstructive sleep apnea are other common identifiable causes,
whereas less common forms of secondary hypertension include
pheochromocytoma, Cushing’s syndrome, hyperparathyroidism and hypoparathyroidism, aortic coarctation, and intracranial tumors (Table 3). The possibility of an identifiable cause of
hypertension increases with age: renal disease, sleep apnea, and
possibly primary aldosteronism are more prevalent among
older patients (13,54).
Patients with documented resistant hypertension should
be evaluated for secondary hypertension if indicated by
clinical and routine laboratory evaluation (11). Description
of the signs and symptoms, diagnostic procedures, and
treatment of identifiable causes of hypertension is beyond
the scope of this article (13).
Pharmacological Treatment
of Resistant Hypertension
Suboptimal dosing regimens or inappropriate antihypertensive drug combinations are the most common causes of
resistant hypertension (52,53). Recommendations on the
modification and intensification of antihypertensive regimens for a given patient taking 3 or more drugs is based on
pharmacological principles in the context of the underlying
pathophysiology that portends hypertension, clinical experience, and available treatment guidelines.
The present rationale for intervention in resistant hypertension (Fig. 2) is to ensure that all possible mechanisms for
Sarafidis and Bakris
Resistant Hypertension
1753
BP elevation are blocked. As volume expansion seems the
most frequent pathogenic finding in these patients (42,55),
an appropriate diuretic to decrease volume overload remains
a cornerstone of therapy (12,16,56). Studies suggest that
changes in diuretic therapy (adding a diuretic, increasing the
dose, or changing the diuretic class based on kidney function) will help ⬎60% of these patients achieve BP goals
(12,42,53,55–57). Thiazide diuretics are effective from
doses of 12.5 mg/day given that kidney function is normal;
increases up to 50 mg may provide additional BP reduction
in some patients (12). Of note, there are differences between
thiazide and thiazide-type diuretics (13,14,58). A recent
trial comparing hydrochlorothiazide 50 mg and chlorthalidone 25 mg daily demonstrated that the latter provided
greater ambulatory BP reduction, with the largest difference
occurring overnight (59). Additionally, a small study of
patients with resistant hypertension demonstrated that
switching from the same dose of hydrochlorothiazide to
chlorthalidone resulted in an additional 8 mm Hg drop in
systolic BP and increased the number of subjects at goal
(60). Unfortunately, chlorthalidone is not commonly available in fixed-dose combinations; therefore, its use will
require separate prescriptions.
The most crucial part of diuretic therapy is to know when
kidney function has deteriorated, so that one may select the
proper class of diuretic. For thiazides, this deterioration is
generally thought to have occurred when the estimated
glomerular filtration rate (eGFR) falls to ⬍50 ml/min/1.73
m2; chlorthalidone can still be effective to an eGFR of ⬇40
ml/min/1.73 m2 if hypoalbuminemia or hyperkalemia is not
present. For patients with eGFR ⬍40 ml/min/1.73 m2, a
loop diuretic should be used (12,13,16). Furosemide or
bumetanide must be given twice daily, and possibly thrice
daily in some cases, as they have short durations of action of
3 to 6 h. Thus, once-daily use is associated with intermittent
natriuresis and consequent reactive sodium retention mediated by increases in the RAS (12,16,61). The loop diuretic
torsemide has a longer duration of action and may be given
once or twice daily (12).
Use of the other drug classes in patients with resistant
hypertension should be based on the general principles of
combination therapy, namely, inhibition of different pathogenic mechanisms, choice of drugs that will compensate for
possible pathophysiological changes evoked by the first
drug, and consideration of compelling indications (11,12).
Moreover, the Food and Drug Administration has recently
approved 3 fixed-dose combination antihypertensive agents
for use as first-line therapy (62). These combinations all
have an agent that blocks the RAS. Fixed-dose antihypertensive combinations are also very useful for patients with
resistant hypertension, especially for those with adherence
problems (63,64).
Ultimately, patient characteristics (age, probable pathogenic mechanisms involved, and concomitant diseases) will
determine the best combination of agents needed to achieve
BP goal. In general, most patients should be on a blocker of
1754
Figure 2
Sarafidis and Bakris
Resistant Hypertension
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
An Approach to Achieving BP Goal in Resistant Hypertension
*Refers to chlorthalidone as the diuretic preferred by the guidelines, namely, thiazide-like. **Vasodilating beta-blockers such as carvedilol and nebivolol have fewer side
effects than traditional beta-blockers such as atenolol, and also have outcome data on heart disease; therefore, they are suggested for better patient adherence.
¶Refers to physicians who are board-certified clinical hypertension specialists. BP ⫽ blood pressure; CCB ⫽ calcium-channel blocker; CKD ⫽ chronic kidney disease;
RAS ⫽ renin-angiotensin system.
the RAS along with a calcium antagonist and an appropriately dosed diuretic. In this case, the physician must ensure
that these agents are prescribed in full dosages, especially for
patients with increased weight, and for appropriate time
intervals. If BP remains above goal, the next step is to add
a fourth agent; a vasodilating beta-blocker is a good choice
if pulse rate is not too low. Peripheral alpha-blockers are
well tolerated and can be used if the beta-blocker selected
does not have alpha-blocking activity.
For true resistant hypertension, there are also good data
to support adding a complementary calcium antagonist to a
regimen including a RAS blocker, diuretic, and calciumchannel blocker (CCB); for example, adding long-acting
diltiazem to nifedipine XL. Such a combination of complementary CCBs results in additive BP reduction with a low
side effect profile and makes pharmacological sense (65,66).
Combining an angiotensin-converting enzyme (ACE)
inhibitor with an angiotensin receptor blocker (ARB) does
not make sense as it was recently shown to be less effective
in terms of BP reduction than was adding a diuretic or a
CCB to an ARB (67), was shown not to reduce cardiovascular or renal events to any greater extent than individual
agents, and may confer increased risk of side effects (68,69).
In a separate trial, the combination of a renin inhibitor
(aliskiren) with an ARB was also associated with a small
additional BP drop (70). Thus, dual RAS blockade is not
recommended for patients with resistant hypertension.
Aldosterone is also part of the RAS, and specific
blockade of aldosterone should be considered in certain
settings. Recent studies suggest that adding spironolactone or eplerenone to existing antihypertensive regimens for
patients with resistant hypertension who are obese or have
sleep apnea provides significant BP reduction (13,71). For
76 patients with uncontrolled BP taking an average of 4
antihypertensive medications, the addition of spironolactone (12.5 to 25 mg daily) resulted in an average 25/12 mm
Hg reduction after 6 months (72). Reductions in BP were
similar in patients with and without primary aldosteronism
and were not predicted by baseline plasma or 24-h urinary
aldosterone, plasma renin activity, or plasma aldosterone/
renin ratio. These data were confirmed by a recent report of
1,411 participants in the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm who were
unselected for plasma aldosterone and renin activity (73)
and who received spironolactone as a fourth-line antihypertensive agent for uncontrolled BP in addition to an average
Sarafidis and Bakris
Resistant Hypertension
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
of 3 drugs. Use of spironolactone resulted in a BP drop of
21.9/9.5 mm Hg that was unaffected by age, sex, smoking,
and diabetic status. Breast tenderness with spironolactone is
common at doses above 25 mg/day but can be avoided with
the use of the more selective mineralocorticoid receptor
antagonist, epleronone (14). Epleronone also has demonstrated BP-lowering efficacy as well as benefits on kidney
disease progression (74).
Amiloride is another potassium-sparing diuretic associated with BP reductions in patients with resistant hypertension (75). When physicians prescribe these agents, especially in combination with an ACE inhibitor or an ARB,
they should monitor potassium levels closely if kidney
function is not within the normal range, and educate the
patient to avoid food and supplements rich in potassium, as
hyperkalemia is a potentially dangerous side effect (14,76).
If BP control is still not achieved with full doses of a
4-drug combination, use of other agents such as centrallyacting alpha-agonists (methyldopa and clonidine) or vasodilators (hydralazine or minoxidil) is needed. These agents
are very effective for lowering BP, but have poor tolerability
and lack of positive outcome data (11). It must be noted,
however, that if therapy has progressed to adding a fourth
agent, referral to a clinical hypertension specialist is warranted (33).
Another class of agents that may prove useful for resistant
hypertension is endothelin-receptor antagonists (ERAs). In
patients with mild-to-moderate essential hypertension, both
nonselective and selective (type A receptor) ERAs produce
BP reductions comparable to those of common antihypertensive agents (77), but concerns about adverse events
precluded their use as a treatment option for uncomplicated
hypertension (78). However, darusentan, a selective ERA
recently tested in 115 patients with resistant hypertension,
demonstrated a dose-dependent decrease in BP. The largest
reductions (11.5/6.3 mm Hg) were observed after 10 weeks
of follow-up with the largest dose, and the drug was
generally well tolerated (78). Ongoing phase III clinical
trials with such agents are awaited to provide further
information in this interesting field.
Conclusions
Although the number of patients who cannot achieve BP
goals on a regimen of multiple medications is growing, the
phenomenon of resistant hypertension is widely understudied, a fact that requires treatment recommendations be
based on pathophysiological principles and clinical experience. Effective management of resistant hypertension requires, first, a careful examination for and exclusion of
factors associated with pseudo-resistance, and second, identification and, when possible, modification of factors related
to true BP elevations. After all of these are successfully
managed, an aggressive treatment regimen designed to
compensate for all mechanisms of BP elevation in a given
patient, most importantly to control volume overload with
1755
proper use of diuretics, will help in moving toward effective
BP control for the majority of patients.
Reprint requests and correspondence: Dr. George L. Bakris,
Hypertensive Diseases Unit, University of Chicago Pritzker
School of Medicine, 5841 South Maryland Avenue, Chicago,
Illinois 60637. E-mail: [email protected].
REFERENCES
1. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and
the United States. JAMA 2003;289:2363–9.
2. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to
lower blood pressure on major cardiovascular events in older and
younger adults: meta-analysis of randomised trials. BMJ 2008;336:
1121–3.
3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific
relevance of usual blood pressure to vascular mortality: a meta-analysis
of individual data for one million adults in 61 prospective studies.
Lancet 2002;360:1903–13.
4. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR.
Development and progression of nephropathy in type 2 diabetes: the
United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney
Int 2003;63:225–32.
5. World Health Organization. World Health Report 2002: Reducing
Risks, Promoting Healthy Life. Geneva, Switzerland: World Health
Organization, 2002.
6. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence,
awareness, treatment, and control of hypertension among United
States adults 1999 –2004. Hypertension 2007;49:69 –75.
7. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment
and control in five European countries, Canada, and the United States.
Hypertension 2004;43:10 –7.
8. Major outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs
diuretic: the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.
9. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention For Endpoint Reduction in
Hypertension Study (LIFE): a randomised trial against atenolol.
Lancet 2002;359:995–1003.
10. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium
antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International
Verapamil-Trandolapril Study (INVEST): a randomized controlled
trial. JAMA 2003;290:2805–16.
11. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the
Joint National Committee on prevention, detection, evaluation, and
treatment of high blood pressure. Hypertension 2003;42:1206 –52.
12. Moser M, Setaro JF. Clinical practice. Resistant or difficult-to-control
hypertension. N Engl J Med 2006;355:385–92.
13. Calhoun DA, Jones D, Textor S, et al. 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. Circulation 2008;117:
e510 –26.
14. Pimenta E, Gaddam KK, Oparil S. Mechanisms and treatment of
resistant hypertension. J Clin Hypertens (Greenwich) 2008;10:
239 – 44.
15. Kaplan NM. Resistant hypertension. J Hypertens 2005;23:1441– 4.
16. Sarafidis PA, Bakris GL. State of hypertension management in the
United States: confluence of risk factors and the prevalence of resistant
hypertension. J Clin Hypertens (Greenwich) 2008;10:130 –9.
17. Sarafidis PA, Li S, Chen SC, et al. Hypertension awareness, treatment, and control in chronic kidney disease. Am J Med 2008;121:
332– 40.
18. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43:
1–290.
1756
Sarafidis and Bakris
Resistant Hypertension
19. Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ.
Blood pressure control and improved cardiovascular outcomes in the
International Verapamil SR-Trandolapril Study. Hypertension 2007;
50:299 –305.
20. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood
pressure measurement in humans and experimental animals. Part 1:
blood pressure measurement in humans. A statement for professionals
from the Subcommittee of Professional and Public Education of the
American Heart Association Council on High Blood Pressure Research. Circulation 2005;111:697–716.
21. Verdecchia P, Schillaci G, Borgioni C, et al. White coat hypertension
and white coat effect. Similarities and differences. Am J Hypertens
1995;8:790 – 8.
22. Brown MA, Buddle ML, Martin A. Is resistant hypertension really
resistant? Am J Hypertens 2001;14:1263–9.
23. Redon J, Campos C, Narciso ML, Rodicio JL, Pascual JM, Ruilope
LM. Prognostic value of ambulatory blood pressure monitoring in
refractory hypertension: a prospective study. Hypertension 1998;
31:712– 8.
24. Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular outcome
in treated hypertensive patients with responder, masked, false resistant,
and true resistant hypertension. Am J Hypertens 2005;18:1422– 8.
25. Caro JJ, Salas M, Speckman JL, Raggio G, Jackson JD. Persistence
with treatment for hypertension in actual practice. CMAJ 1999;160:
31–7.
26. Mazzaglia G, Mantovani LG, Sturkenboom MC, et al. Patterns of
persistence with antihypertensive medications in newly diagnosed
hypertensive patients in Italy: a retrospective cohort study in primary
care. J Hypertens 2005;23:2093–100.
27. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. Rate and
determinants of 10-year persistence with antihypertensive drugs.
J Hypertens 2005;23:2101–7.
28. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence
to prescribed antihypertensive drug treatments: longitudinal study of
electronically compiled dosing histories. BMJ 2008;336:1114 –7.
29. Haynes R, Yao X, Degani A, et al. Interventions to enhance medication adherence. Cochrane Database Syst Rev 2005;CD000011.
30. Takiya LN, Peterson AM, Finley RS. Meta-analysis of interventions
for medication adherence to antihypertensives. Ann Pharmacother
2004;38:1617–24.
31. Singer GM, Izhar M, Black HR. Goal-oriented hypertension management: translating clinical trials to practice. Hypertension 2002;40:
464 –9.
32. Phillips LS, Branch WT, Cook CB, et al. Clinical inertia. Ann Intern
Med 2001;135:825–34.
33. Trewet CL, Ernst ME. Resistant hypertension: identifying causes and
optimizing treatment regimens. South Med J 2008;101:166 –73.
34. Hyman DJ, Pavlik VN. Self-reported hypertension treatment practices
among primary care physicians: blood pressure thresholds, drug
choices, and the role of guidelines and evidence-based medicine. Arch
Intern Med 2000;160:2281– 6.
35. Oliveria SA, Lapuerta P, McCarthy BD, L’Italien GJ, Berlowitz DR,
Asch SM. Physician-related barriers to the effective management of
uncontrolled hypertension. Arch Intern Med 2002;162:413–20.
36. O’Brien E, Asmar R, Beilin L, et al. Practice guidelines of the
European Society of Hypertension for clinic, ambulatory and self
blood pressure measurement. J Hypertens 2005;23:697–701.
37. Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens (Greenwich) 2008;10:556 – 66.
38. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal antiinflammatory drugs affect blood pressure? A meta-analysis. Ann Intern
Med 1994;121:289 –300.
39. Conlin PR, Moore TJ, Swartz SL, et al. Effect of indomethacin on
blood pressure lowering by captopril and losartan in hypertensive
patients. Hypertension 2000;36:461–5.
40. Bakris GL, Kern SR. Renal dysfunction resulting from NSAIDs. Am
Fam Physician 1989;40:199 –204.
41. Whelton A, White WB, Bello AE, Puma JA, Fort JG. Effects of
celecoxib and rofecoxib on blood pressure and edema in patients ⬎ or ⫽
65 years of age with systemic hypertension and osteoarthritis. Am J
Cardiol 2002;90:959 – 63.
42. Graves JW, Bloomfield RL, Buckalew VM Jr. Plasma volume in
resistant hypertension: guide to pathophysiology and therapy. Am J
Med Sci 1989;298:361–5.
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
43. Nishizaka MK, Pratt-Ubunama M, Zaman MA, Cofield S, Calhoun
DA. Validity of plasma aldosterone-to-renin activity ratio in African
American and white subjects with resistant hypertension. Am J
Hypertens 2005;18:805–12.
44. Vollmer WM, Sacks FM, Ard J, et al. Effects of diet and sodium
intake on blood pressure: subgroup analysis of the DASH-sodium
trial. Ann Intern Med 2001;135:1019 –28.
45. Bramlage P, Pittrow D, Wittchen HU, et al. Hypertension in
overweight and obese primary care patients is highly prevalent and
poorly controlled. Am J Hypertens 2004;17:904 –10.
46. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood
pressure control in diverse North American settings: the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393– 404.
47. Morris MJ. Cardiovascular and metabolic effects of obesity. Clin Exp
Pharmacol Physiol 2008;35:416 –9.
48. Sarafidis PA. Obesity, insulin resistance and kidney disease risk:
insights into the relationship. Curr Opin Nephrol Hypertens 2008;17:
450 – 6.
49. Wong C, Marwick TH. Obesity cardiomyopathy: pathogenesis and
pathophysiology. Nat Clin Pract Cardiovasc Med 2007;4:436 – 43.
50. Aucott L, Poobalan A, Smith WC, Avenell A, Jung R, Broom J.
Effects of weight loss in overweight/obese individuals and long-term
hypertension outcomes: a systematic review. Hypertension 2005;45:
1035– 41.
51. Calhoun DA, Zaman MA, Nishizaka MK. Resistant hypertension.
Curr Hypertens Rep 2002;4:221– 8.
52. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care
clinic. Arch Intern Med 1991;151:1786 –92.
53. Garg JP, Elliott WJ, Folker A, Izhar M, Black HR. Resistant
hypertension revisited: a comparison of two university-based cohorts.
Am J Hypertens 2005;18:619 –26.
54. Anderson GH Jr., Blakeman N, Streeten DH. The effect of age on
prevalence of secondary forms of hypertension in 4429 consecutively
referred patients. J Hypertens 1994;12:609 –15.
55. Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing
hemodynamic management to specialist care. Hypertension 2002;39:
982– 8.
56. Jamerson K, Bakris GL, Dahlof B, et al. Exceptional early blood
pressure control rates: the ACCOMPLISH trial. Blood Press 2007;
16:80 – 6.
57. Black HR, Elliott WJ, Grandits G, et al. Principal results of the
Controlled Onset Verapamil Investigation of Cardiovascular End
Points (CONVINCE) trial. JAMA 2003;289:2073– 82.
58. Handler J. Maximizing diuretic therapy in resistant hypertension.
J Clin Hypertens (Greenwich) 2007;9:802– 6.
59. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive
effects of hydrochlorothiazide and chlorthalidone on ambulatory and
office blood pressure. Hypertension 2006;47:352– 8.
60. Khosla N, Chua DY, Elliott WJ, Bakris GL. Are chlorthalidone and
hydrochlorothiazide equivalent blood-pressure-lowering medications?
J Clin Hypertens (Greenwich) 2005;7:354 – 6.
61. Sarafidis PA. Proteinuria: natural course, prognostic implications and
therapeutic considerations. Minerva Med 2007;98:693–711.
62. Medical News Today. FDA approves first combination therapy for
initial use in patients with moderate to severe hypertension. Available
at: http://www.medicalnewstoday.com/articles/89340.php. Accessed
August 15, 2008.
63. Khanna A, Lefkowitz L, White WB. Evaluation of recent fixed-dose
combination therapies in the management of hypertension. Curr Opin
Nephrol Hypertens 2008;17:477– 83.
64. Dickson M, Plauschinat CA. Racial differences in medication compliance and healthcare utilization among hypertensive Medicaid recipients: fixed-dose vs free-combination treatment. Ethn Dis 2008;18:
204 –9.
65. Saseen JJ, Carter BL, Brown TE, Elliott WJ, Black HR. Comparison
of nifedipine alone and with diltiazem or verapamil in hypertension.
Hypertension 1996;28:109 –14.
66. Gashti CN, Bakris GL. The role of calcium antagonists in chronic
kidney disease. Curr Opin Nephrol Hypertens 2004;13:155– 61.
67. Stergiou GS, Makris T, Papavasiliou M, Efstathiou S, Manolis A.
Comparison of antihypertensive effects of an angiotensin-converting
enzyme inhibitor, a calcium antagonist and a diuretic in patients with
JACC Vol. 52, No. 22, 2008
November 25, 2008:1749–57
68.
69.
70.
71.
72.
73.
hypertension not controlled by angiotensin receptor blocker monotherapy. J Hypertens 2005;23:883–9.
Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients
at high risk for vascular events. N Engl J Med 2008;358:1547–59.
Mann JF, Schmieder R, McQueen M, et al. Renal outcomes with
telmisartan, ramipril, or both in people at high vascular risk: results
from a multicenter, randomised, double-blind, controlled trial. Lancet
2008;372:547–53.
Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and
safety of combined use of aliskiren and valsartan in patients with
hypertension: a randomised, double-blind trial. Lancet 2007;370:221–9.
Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS,
Harding SM, Calhoun DA. Plasma aldosterone is related to severity of
obstructive sleep apnea in subjects with resistant hypertension. Chest
2007;131:453–9.
Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose
spironolactone in subjects with resistant hypertension. Am J Hypertens
2003;16:925–30.
Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on
blood pressure in subjects with resistant hypertension. Hypertension
2007;49:839 – 45.
Sarafidis and Bakris
Resistant Hypertension
1757
74. Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone,
enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003;108:1831– 8.
75. Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP.
Low-renin status in therapy-resistant hypertension: a clue to efficient
treatment. J Hypertens 2004;22:2217–26.
76. Calhoun DA. Resistant or difficult-to-treat hypertension. J Clin
Hypertens (Greenwich) 2006;8:181– 6.
77. Nakov R, Pfarr E, Eberle S. Darusentan: an effective endothelin A
receptor antagonist for treatment of hypertension. Am J Hypertens
2002;15:583–9.
78. Black HR, Bakris GL, Weber MA, et al. Efficacy and safety of
darusentan in patients with resistant hypertension: results from a
randomized, double-blind, placebo-controlled dose-ranging study.
J Clin Hypertens (Greenwich) 2007;9:760 –9.
Key Words: resistant hypertension y management y evaluation y
treatment.