REVIEWS

Resistant Arterial Hypertension Yet another Problem for Clinical Practice

ELISABETA BDIL1, 2, ANA MARIA DARABAN1, EMMA INTEA1,
CRISTINA MANUELA TRZIU1, MIHAELA HOSTIUC1, 2, DANIELA BARTO1, 2
1

Clinical Department of Internal Medicine, Floreasca Clinical Emergency Hospital Bucharest,

Romania
2
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Unfortunately, in a high percentage of hypertensive patients blood pressure control cannot be

achieved even with extensive medical treatment, leaving them at a much higher risk for major
cardiovascular events. Until recently therapeutic resources for such patients were scarce. One must
keep in mind that many hypertensives are under suboptimal treatment, do not respect diet and are
refractory to making major life-style changes. The referring physician must exclude secondary causes
of hypertension such as sleep apnea, renal artery stenosis, primary aldosteronism or advanced chronic
renal disease. However, two major minimally invasive procedures have been put into practice, namely
the recently approved renal denervation and the electrical stimulation of carotid sinus barroreceptors.
The first mentioned has gained many followers lately, and has been proven effective in several
clinical trials, and promises to obtain good blood pressure control in patients otherwise resistant to
extensive medical therapy.
Key words: resistant arterial hypertension, renal denervation, secondary hypertension, pseudoresistance.

Arterial hypertension (HTN) is still a major

public health problem, affecting approximately
one-quarter of all adults in developed countries [1].
It is the leading cause of mortality worldwide and it
is also responsible for approximately 7.1 million
deaths per year [2]. Arterial hypertension is an
important cardiovascular risk factor, as each increase
by 20/10 mmHg in blood pressure doubles the
cardiovascular mortality rate [3]. However, HTN
cannot be controlled by pharmacological and nonpharmacological methods in 19 to 40% of cases,
depending on the country, leaving a significant
proportion of patients vulnerable to the risk of
cardiovascular events [4].
Moreover, there is a subgroup of HTN patients
who never reach the target blood pressure values in
spite of taking all the steps to change their lifestyle
and despite the use of many drugs. This condition
is known as refractory or resistant arterial hypertension, when target BP values (lower than 140/90
mmHg or 135/85 mmHg in diabetics, chronic renal
disease or cardio-vascular atherosclerosis) cannot
be reached despite proper treatment using at least
three drugs in optimum dosage, one of them being
a diuretic [5]. Although the number of drugs from
which HTN is considered to be resistant was
somewhat arbitrarily chosen, the main objective in
defining this clinic entity was to identify those
ROM. J. INTERN. MED., 2013, 51, 1, 918

patients at high risk of having a reversible cause of

HTN and/or patients who, because of persistent
elevated blood pressure levels, can benefit from
special diagnostic or therapeutic approaches.
In patients with resistant HTN both systolic
and diastolic BP values can be elevated but, in
general, there is a higher prevalence of systolic
hypertension, as the ALLHAT study showed, in
which BP target values were achieved only in 67%
of cases, as compared to 92% of cases in which
diastolic BP target values were reached [6].
Resistant arterial hypertension is synonymous
with refractory hypertension, but it is not synonymous
to uncontrolled hypertension. In this case, the
resistant hypertension is not the only cause of
uncontrolled HTN, as inappropriate treatment
and/or pseudo-resistance must be excluded [5].
Pseudo-resistance is caused by lack of adherence to
medication in uncooperative patients, incorrect BP
measurement or white coat hypertension. White
coat hypertension can be seen in 20 to 30% of
patients, leading to a flawed diagnosis [7].
The real prevalence of resistant HTN is
unknown. In a study conducted in the United States
of America (USA) including approximately 16.000
patients, 8.9% met the diagnostic criteria for
resistant hypertension [8]. Other studies indicate a
prevalence of 12.3% (Spain) and 16% (South-

10

Elisabeta Bdil et al.

eastern USA) [9]. In the recent period, we have

also witnessed an increase in difficult-to-control
HTN possibly as a result of the increase in weight
and life span [10].
RISK FACTORS FOR RESISTANT HYPERTENSION

There are some characteristics in the profile

of a HTN patient which can lead to difficulties in
controlling HTN, namely: obesity, high blood
pressure levels at the moment of diagnosis, isolated
systolic hypertension, left ventricular hypertrophy
(LVH), African-American race, age, diabetes or
chronic renal disease [6]. There is a number of
potentially reversible factors that contribute to
resistant hypertension, mainly: suboptimal treatment,
lifestyle and diet, the combination of drugs or
herbal recipes that increase blood pressure values,
and also the presence of secondary hypertension
[5].
SUBOPTIMAL TREATMENT

This is a frequent cause of uncontrolled

hypertension, whether it is under the form of a
medication of insufficient antihypertensive potency
or the omission of diuretic therapy that could
prevent extracellular volume expansion which is
sometimes responsible for the resistance to therapy.
Reports have shown that only 1827% of patients
with uncontrolled hypertension were receiving at
least three antihypertensive drugs, one of which
was a diuretic [11].
LIFESTYLE AND DIET

Obesity, salt-rich diet, physical inactivity,

excessive intake of alcohol are all factors which
contribute, on the one hand, to HTN development,
and, on the other hand, to its resistance to therapy.
Salt intake control alone can lead to an average
decrease in the office BP of 23/9 mmHg [12].
MEDICATION

It is well known that there are drugs which

can increase BP, or, in some cases, limit the effects
of hypotensive medication. Non-steroidal antiinflammatory drugs (NSAIDs), including COX-2
selective inhibitors, and aspirin, may increase BP
by reducing sodium excretion and secondary increase
in intravascular volume. These drugs interfere with
antihypertensive agents, with the exception of

calcium blockers [11]. Other drugs cited for their

hypertensive effect include: corticosteroids, especially
those having a strong mineralocorticoid effect
(cortisone, hydrocortisone), sympathomimetic agents
(decongestants, anorexogenic drugs, cocaine), stimulants (amphetamine, methylphenidate), alcohol,
oral contraceptives, cyclosporine or some herbs
(ephedra). In patients with chronic kidney disease
and anemia, the use of erythropoietic agents may
increase blood pressure. The use of vasodilator
drugs can also cause a reflex increase in sodium
reabsorption leading to an increase in circulating
volume, thus changing the blood pressure [6].
SECONDARY HYPERTENSION

When not recognized from the beginning, this

may be another cause of resistance to treatment.
The prevalence of these secondary causes of
hypertension is unknown but it is more likely to be
found in the elderly, in which sleep apnea is more
frequent, along with renal disease, renal artery
stenosis and possibly primary aldosteronism. Rare
causes of secondary hypertension are pheochromocytoma, Cushings syndrome, hyperparathyroidism,
coarctation of the aorta and cranial tumors [6].
Sleep apnea
This is quite common in patients with
resistant hypertension, with a higher severity in
men than in women and an inverse correlation
between sleep apnea severity and the likelihood to
control blood pressure. The mechanism involved is
not yet completely elucidated but it is probably
related to the activation of the sympathetic nervous
system during the sleep apnea episode [13]. Under
these circumstances, when we have an obese
patient with daytime sleepiness and resistant hypertension, polysomnography is useful to discover
sleep apnea. In diagnosed cases, applying a C-PAP
(Continuous Positive Airway Pressure) mask can
improve the response to antihypertensive treatment.
Primary aldosteronism
This should be suspected in patients with
persistent hypokalemia. Even though often, in
clinical practice, hypokalemia is attributed to the
diuretic treatment, in the case of resistant hypertension one must explore the patient in order to
diagnose a possible endocrine disorder. One should
also notice that only about 50% of patients with
primary aldosteronism have hypokalemia, thus
suggesting that this is a late manifestation of the

Resistant arterial hypertension

disease, preceded by the development of hypertension [14]. Recent studies show that primary
hyperaldosteronism is much more common than
previously thought, with an average prevalence of
up to 6.1% in the hypertensive population. The
prevalence increases with HTN severity, thus
doubling in the group of patients with blood
pressure levels over 180/110 mmHg [15].
Renal artery stenosis
This is a relatively common cause of resistance
to treatment and may be represented by an
atherosclerotic lesion, in 90% of cases, often found
in elderly people, smokers, patients diagnosed with
peripheral arterial disease or renal failure of
unknown cause or, more rarely, fibromuscular
dysplasia which tends to affect women younger
than 50 years with uncontrolled high blood
pressure [5].
Chronic kidney disease
This is both a cause and a complication of
uncontrolled hypertension. As the kidney disease
progresses the number of hypotensive drugs
required to control the HTN increases, as the
ALLHAT study revealed, in which a creatinine
value above 1.5 mg/dL was a significant predictor
of failure to achieve target blood pressure values
[6]. In patients with chronic kidney disease,
resistance to treatment is largely related to increased
sodium retention and extracellular volume expansion,
thus emphasizing the importance of diuretic
therapy in hypertension control in these patients.
The other rare causes of secondary hypertension should be known and reviewed whenever
blood pressure values are not controlled and the
most frequent causes of resistance to therapy are
excluded.
DIAGNOSIS OF RESISTANT HYPERTENSION

In order to include a patient in the resistant

hypertension group, one should confirm that the
resistance is real, look for causes contributing to
resistance development and evaluate organ damage
left ventricle hypertrophy, microalbuminuria,
retinopathy, etc. One should also rule out pseudoresistance both through proper measurements of
blood pressure and ensuring patients compliance
to treatment.

11

Patient compliance to treatment is of paramount importance. Therefore, it is necessary to

specifically ask the patient whether he or she
managed to take the medicine, whether there were
any difficulties related to its cost or its side effects
that may have prevented him or her to follow the
prescribed therapy. The family may also contribute
to the history to give more objective data about
adherence to treatment.
One must not forget when evaluating HTN
resistant patients that history taking is a very
important element, not only in assessing adherence
to treatment, but also establishing the coexistence of
other medications that may increase or decrease the
effect of the hypotensive treatment, or the presence
of symptoms suggestive for sleep apnea, such as
daytime sleepiness, snoring or a history of atherosclerotic artery disease that would increase the
likelihood of renal artery stenosis.
The physical examination must be carried
out carefully in order to reveal any changes
suggestive for secondary hypertension. For example,
murmurs from carotid or femoral arteries may also
suggest an atherosclerotic renal artery stenosis;
differences in blood pressure values between upper
and lower limbs may be suggestive for coarctation
of the aorta, while the presence of a full moon
facies, abdominal obesity and striae may suggest
Cushing Syndrome.
In order to properly diagnose resistant hypertension it is of utmost importance to correctly
measure blood pressure and rule out white coat
hypertension. This can be properly achieved by
installing a 24 h blood pressure monitor in ambulatory conditions. The white coat effect should be
suspected in patients with BP values consistently
higher than those recorded in ambulatory conditions
who have no signs of organ damage. These
categories of patients are candidates for 24 h blood
pressure monitoring in ambulatory settings [5].
Laboratory testing in a patient suspected
with resistant hypertension must include: serum
and urine electrolytes (sodium, potassium), blood
glucose, creatinine and creatinine clearance rate,
urine test, 24 h urine proteins [5].
Considering recent data suggesting a relatively
high prevalence of primary aldosteronism in the
hypertensive population with difficult to control
values of BP, it is recommended to screen for this
condition by measuring both plasma aldosterone
concentration (PAC) and plasma renin activity
(PRA) and the PAC/PRA ratio. In normal subjects
and patients with essential hypertension, the
PAC/PRA ratio lies between 4 and 10 [16, 17].

12

Elisabeta Bdil et al.

Thus, a PAC/PRA ratio over 20 (when PAC is

expressed in nanograms per deciliter and PRA in
nanograms per milliliter) is suggestive for primary
aldosteronism and further medical investigation is
needed to confirm the diagnosis. With the exception
of aldosterone-receptor-blocking drugs, even in the
presence of hypotensive therapy, this ratio is a
useful screening test with a high negative predicttive value [16]. If the patient is receiving aldosterone-receptor-blocking diuretics, they should be
discontinued for at least 6 weeks before testing,
with an emphasis on the importance of spironolactone or eplerenone initiation once the assessment
of the hypertensive patient is complete (Fig. 1).
Sodium, potassium and aldosterone levels in
a 24 h urine sample should also be measured.
Sodium urine levels will help assess whether the
patient respects a salt restricted diet, unless diuretic
therapy has not been initiated in the last two weeks
or if during this period the diuretic dosage has not
been increased.
In other patients with resistant hypertension,
who associate events such as palpitations, tremors,
sweating, screening for pheochromocytoma is also
advised. This includes measuring metanephrines
and catecholamine levels in a 24 h urine sample
and/or free plasma metanephrines [5].
In some patients with atherosclerotic coronary
disease or peripheral artery disease, who present
with resistant hypertension, certain imaging tests
should be conducted in order to detect a possible
renal artery stenosis (venous Doppler ultrasonography, angio-MRI or renal arteriography). These
tests are even more necessary when the patient has
been found with high levels of serum creatinine
after initiating therapy with angiotensin converting
enzyme inhibitors (ACEI) or angiotensin receptor
blockers (ARB).
In a proper clinical context and in the absence
of other causes that might have been revealed by
the tests discussed above, the physician will also
investigate for the presence of a possible Cushings
syndrome, an aortic coarctation or the presence of
hyperparathyroidism.
RESISTANT HYPERTENSION THERAPY

Resistant hypertension usually presents with

a multifactorial etiology and therefore the treatment
is composed of several pharmacological or nonpharmacological components.
A major component of resistant hypertension
treatment is the identification and treatment of

reversible or curable causes of secondary hypertension (sleep apnea syndrome, parenchymal renal
disease, primary aldosteronism, renal artery stenosis,
pheochromocytoma, Cushings syndrome, hyperparathyroidism, coarctation of the aorta) [5].
Another step is to stop using drugs that
interfere with hypotensive treatment or that can
increase BP levels, or to reduce their dosage to a
minimum active level (NSAIDs, including COX-2
inhibitors, aspirin, decongestant sympathomimetics,
cocaine, anorexogenics, alcohol, oral contraceptives, cyclosporine or natural plant extract like
ephedra or ma huang).
In resistant hypertension too, the nonpharmacological measures are useful. However, no
specific studies have been conducted for this form
of hypertension. The measures include weight loss
in overweight or obese patients, dietary salt
restriction, limiting alcohol consumption, regular
physical activity and fiber rich low fat diets (DASH
diet Dietary Approaches to Stop Hypertension)
[5, 7, 18].
PHARMACOLOGICAL TREATMENT

By definition, a patient with resistant hypertension receives at least three hypotensive drugs,
one of which is a diuretic. A major role in the
treatment of resistant hypertension is to improve
patient adherence to prescribed antihypertensive
medication. It is thus recommended to use fixed
combinations of drugs with prolonged action,
which allow single daily administration. Moreover,
encouraging the patient to take responsibility and
get involved in the therapeutic process by keeping
a log of blood pressure levels leads to an increased
adherence to treatment and a greater family
involvement, which will also contribute to patient
compliance [19].
Diuretics have a significant role in the
treatment of resistant hypertension. A study of 279
patients with resistant hypertension, of which 85%
were receiving a thiazide diuretic, showed significantly higher levels of BNP (brain natriuretic
peptide) and ANP (atrial natriuretic peptide) in
those with resistant hypertension as compared to
control, therefore suggesting the presence of
volume expansion [20]. Under these circumstances,
even in patients without edema and on conventional-dose thiazide diuretics, one can suspect a
certain degree of extracellular volume expansion
contributing to the development of resistant
hypertension.

Resistant arterial hypertension

13

Figure 1. Resistant hypertension diagnostic algorithm adapted from the AHA Professional Education Committee of the Council for
High Blood Pressure Research. BP blood pressure; CKD chronic kidney disease; DM diabetes mellitus; HTN hypertension.

There are studies comparing 25 mg of chlorthalidone with 50 mg hydrochlorothiazide, and

showing a greater decrease of blood pressure levels
when using the first one, especially during the
night [21]. Thus, chlorthalidone is recommended
instead of hydrochlorothiazide. The treatment is

initiated with 12.5 mg and afterwards increased up

to 25 mg/day, with careful monitoring of electrolyte levels.
Furosemide or torasemide are indicated in
patients with a creatinine clearance ratio below
30mL/min/m2 which greatly decreases the effect of

14

Elisabeta Bdil et al.

thiazide diuretic. As it is a short-acting diuretic,

furosemide should be administered at least twice a
day. The use of a long-acting loop diuretic such as
torasemide is limited by its high cost and availability in some European countries [10].
Aldosterone antagonists (spironolactone,
eplerenone, amiloride) added to the therapy of
patients with resistant hypertension can lead to
blood pressure control. This is due to the fact that
aldosterone levels are increased in these patients as
compared to those with controlled or normal blood
pressure. The antihypertensive effect of spironolactone was evaluated in the ASCOT study on 1411
patients who had uncontrolled hypertension under
therapy with three hypotensive drugs (average BP
157/85 mmHg). In this study, adding the fourth
drug spironolactone led to a decrease in blood
pressure of 21.9/9.5 mmHg at one-year follow-up,
with hyperkalemia found in 4% of patients [22]. In
another study, carried out in a hypertension
specialized university center, adding spironolactone
to the treatment of patients with resistant hypertension led to a decrease in BP of 25/12 mmHg. It
is interesting to note that this decrease could not be
predicted by the serum aldosterone levels, plasma
renin activity or aldosterone excretion in a 24 h
urine sample [23]. During spironolactone therapy,
serum potassium levels must be recorded as there is
a risk for hyperkalemia in patients with chronic
kidney disease or in those on ACEI/ARB or
NSAIDs.
There are many studies proving the effectiveness of combining two hypotensive drugs, but there
is few data on the effectiveness of a specific
combination of three antihypertensive drugs. Thus,
multidrug therapy is somewhat empirical. It is
intuitively appropriate to combine drugs with
different action mechanisms. Thus, in a patient
with resistant hypertension the combination of an
ACEI or ARB with a dihydropyridine calcium
channel blocker (amlodipine) and a long-acting
thiazide diuretic (chlorthalidone) is effective and
generally well tolerated [5]. If blood pressure levels
are not controlled with this triple combination, one
can add spironolactone, 12.5 mg initially, and
increase the dose up to 50mg/day. Exceeding this
dose is recommended only in primary aldosteronism.
Although beta-blockers are indicated in
patients with ischemic heart disease and heart
failure, the use of alpha-blockers seems more
effective in patients who already receive three of
the recommended hypotensive drugs and need to

add a fourth: labetalol or carvedilol, considering

their dual action both cardiac depressants and
vasodilators, even if there are no studies to directly
compare adrenal blockers in resistant hypertension
therapy [24].
Another class of antihypertensive agents is
that of central acting agents such as clonidine,
guanfacine, reserpine, which have a significant
hypotensive effect but also a higher rate of adverse
reactions [5].
As a final therapeutic measure for those who
do not respond to the recommended therapies, one
can combine direct vasodilators hydralazine-like
and minoxidil. The latter shows side effects such as
fluid retention and tachycardia, and therefore often
requires the association of a loop diuretic and a
beta blocker. Minoxidil may also cause hirsutism,
and thus, especially in women, should be replaced
by hydralazine [10].
MINIMALLY INVASIVE PROCEDURES

Renal denervation by radiofrequency

catheter ablation
Based on the fact that the sympathetic
nervous system plays an essential role in the
development and progression of hypertension,
researchers have sought ways to act on it in order
to control BP [25, 26]. Normally, sympathetic
activation in the kidney will reduce renal blood
flow through vasoconstriction; it will increase
tubular sodium resorption, leading to sodium
retention and the increase of plasma volume and
renin secretion from the juxtaglomerular apparatus,
with a direct effect the activation of the reninangiotensin-aldosterone system. This cascade of
efferent sympathetic responses is caused either by
renal ischemia or renal damage. The fact that the
increased sympathetic activity stands at the basis of
arterial hypertension has created the premises for
researchers to attempt to modulate this system.
Experimental models using renal denervation have
confirmed the possibility of decreasing blood
pressure. There have been several attempts to limit
the sympathetic action on kidneys in humans.
Between 1920 and 1930, radical splahnicectomy
and sympathectomy was practiced in patients with
severe hypertension [27, 28]. A more selective
procedure involving the sole removal of the lymph
nodes with efferent fibers to the kidneys is the
GRIMSON procedure. It is however followed by
periprocedural complications [29].

Resistant arterial hypertension

Catheter-based renal sympathetic denervation

is a newer technique that involves inserting a
percutaneous catheter in the renal artery. The
electrode is positioned through the catheter directly
in contact with the vessel wall. Afterwards, over six
longitudinal and circular radiofrequency ablations
are carried out in each renal artery. The procedure
is followed by a significant decrease in blood
pressure. The results of studies on patients with
renal denervation by radiofrequency catheter ablation
are encouraging, as BP values remain at low levels
24 months after the procedure, with a constant
renal function, estimated by glomerular filtration
rate and nystatin C levels, allowing the decrease in
the number of drugs used for BP control [30, 31].
Despite encouraging results, it remains to be seen
whether the procedure is beneficial on a long term,
knowing that sympathetic fibers can regenerate. It
is also necessary to adapt the ablation technique on
patients with abnormal renal vascularization (double
renal artery or accessory arteries) and in those with
renal artery stenosis.
The growing importance of renal denervation
for HTN treatment is underlined by the recent
publication of a statement paper from ESH
(European Society of Hypertension) regarding
efficacy, safety and eligibility of patients for the
above mentioned procedure [32]. According to the
current statement paper, hypertensive patients are
eligible for RDN if they have (severe) treatmentresistant hypertension, defined by office SBP at
least 160 mmHg ( 150 mmHg in type 2 diabetes)
despite treatment with at least three antihypertensive
drugs of different types in adequate doses,
including one diuretic, which is equivalent to stage
2 or 3 hyper-tension. Here again it is emphasized
that clear distinction between pseudoresistance and
true severe HTN is of paramount importance and
that the patients should be first investigated
thoroughly by a hypertension specialist from
experienced hypertension centers. After correct and
complete diagnosis, the patient should be on
maximal anti-HTN therapy as recommended by the
guidelines and all lifestyle factors that influence
response to therapy should be corrected. It is still of
debate if patients should first receive an
aldosterone antagonist (e.g. spironolactone) drug
before proceeding to RND.
Only after these steps are undertaken, patients
should be evaluated for suitability of the intervention. If not done before, it is recommended to
obtain renal artery imaging [e.g. CT or magnetic

15

resonance (MR) angiography] to assess accurately

renal artery anatomy before performing RDN.
If the anatomical criteria are met then
exclusion criteria should also be implemented in
order to safely proceed to RDN as recommended in
the ESH statement paper:
1. Previous renal artery intervention (balloon
angioplasty or stenting),
2. Evidence of renal artery atherosclerosis
(defined as a renal artery stenosis >50%),
3. Presence of multiple main renal arteries in
either kidneys or main renal arteries of less than
4 mm in diameter or less than 20 mm in length.
4. Estimated glomerular filtration rate <
45 ml/min per 1.73 m2.
5. Patients should be in stable clinical
conditions thus ruling out patients with recent
myocardial infarction, unstable angina pectoris, or
a cerebrovascular accident within the past 3
6 months.
The intervention should be performed by
trained cardiologists or radiologists for this specific
intervention and who are qualified to manage
potential complications, such as dissection of renal
artery.
This modern technique for the therapy of
HTN, especially in the resistant form, could be
evaluated in other forms too, namely in patients
with hypertension and intolerance to medication or
those who are not compliant to treatment. This
technique offers new perspectives for therapy of
patients in final stages of renal failure where there
are increased levels of noradrenaline with known
consequences: hypertension, left ventricular hypertrophy, ventricular arrhythmias and sudden cardiac
death. Obesity, insulin resistance and diabetes are
other entities that are often associated with
increased sympathetic activity. Applying sympathetic
denervation therapy in these cases may prevent
diabetic nephropathy. It is thus obvious that renal
denervation is a technique whose effects are still
little known and practiced [33].
Electrical stimulation of carotid sinus
baroreceptors
This is a technique that can reduce BP in
patients with resistant hypertension. Even if results
show a decrease in blood pressure levels after
stimulation device implantation, this technique is
not yet recommended as a therapeutic procedure,
due to the small number of patients to whom this
procedure has been applied [34].

16

Elisabeta Bdil et al.

CONCLUSIONS

Resistant hypertension is still a problem for

clinical practice as the number of patients that
reach blood pressure targets is disappointingly low.
Patients that meet the diagnostic criteria for
resistant HTN should be investigated thoroughly to
exclude causes of pseudoresistance and care should
be taken that all lifestyle factors that negatively
influence response to therapy are corrected. The
next mandatory step is the initiation of an
aggressive treatment regimen designed to compensate for all mechanisms of BP elevation in a given

patient. If all these measures fail to control BP

levels, interventional treatment should be taken into
account after carefully reviewing the indications
and contraindications of such procedures. Until
new therapeutic methods will be applied in more
numerous medical centers and more research will
emphasize the benefit of other techniques, treating
resistant hypertension remains a serious problem,
because these patients have severe organ damage
and a higher risk of stroke, myocardial infarction or
heart failure than those with controlled hypertension.

Controlul valorilor tensionale nu poate fi uneori atins chiar sub terapie

farmacologic maximal la un procent semnificativ de pacieni hipertensivi, expui
astfel unui risc crescut de apariie a evenimentelor cardiovasculare majore. Pn
de curnd, resursele terapeutice n cazul acestui tip de pacieni au fost relativ
limitate. De reinut c totui o parte dintre aceti pacieni au o fals rezisten la
tratament fie c nu se afl sub tratament medicamentos optim maximal, fie refuz
s fac schimbrile majore n stilul de via necesare unui control tensional
adecvat. n plus, n faa suspiciunii de hipertensiune rezistent, medicul curant
trebuie s exclud, rnd pe rnd, cauzele secundare de hipertensiune, cum sunt:
sindromul de apnee n somn, stenoza de arter renal, hiperaldosteronismul
primar, boala cronic de rinichi. Dou proceduri majore minim invazive au fost
propuse i introduse n practica medical n vederea obinerii unui control
tensional adecvat la aceti pacieni: denervarea renal, recent aprobat pentru
practica medical n Europa, i stimularea electric a baroreceptorilor sinusului
carotidian. Denervarea renal, n special, s-a dovedit eficient n numeroase
trialuri clinice n ultimii ani, procedura fiind urmat de scderea semnificativ a
valorilor tensionale la pacieni considerai rezisteni la terapia medicamentoas
maximal.

Corresponding author: Dr. Elisabeta Badila, Clinical Department of Internal Medicine,

Clinical Emergency Hospital Bucharest, Calea Floreasca nr. 8, Sector 1, Bucharest
E-mail: elisabeta.badila@gmail.com
REFERENCES
1.
2.
3.
4.
5.

6.

WOLF-MAIER K., COOPER R.S., BANEGAS JR. et al., Hypertension prevalence and blood pressure levels in 6 European
countries, Canada, and the United States. 2003, JAMA, vol. 289, p. 23632369.
World Health Organization. Reducing Risks, Promoting Healthy Life. Geneva: World Health Organization, 2002.
VASAN R.S., LARSON M.G., LEIP E.P. et al., Assessment of frequency of progression to hypertension in nonhypertensive
participants in the Framingham Heart Study: a cohort study. JAMA, 2001, vol. 358, p. 16821686.
WOLF-MAIER K., COOPER R.S., KRAMER H. et al., Hypertension treatment and control in five European countries,
Canada, and the United States. Hypertension, 2004, vol. 43, p. 1017.
CALHOUN D.A., 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. Hypertension, 2008, vol. 51, p. 14031419.
CUSHMAN W.C., FORD C.E., CUTLER J.A., MARGOLIS K.L., DAVIS B.R., GRIMM R.H., BLACK H.R., HAMILTON
B.P., HOLLAND J., NWACHUKU C., PAPADEMETRIOU V., PROBSTFIELD J., WRIGHT J.T., ALDERMAN M.H., WEISS
R.J., PILLER L., BETTENCOURT J., WALSH S.M., for the ALLHAT Collaborative Research Group. Success and predictors of

7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.

20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.

Resistant arterial hypertension

17

blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering and Treatment to Prevent
Heart Attack Trial (ALLHAT). J Clin Hypertens, 2002, vol. 4, p. 393404.
BROWN M.A., BUDDLE M.L., MARTIN A., Is resistant hypertension really resistant? Am. J. Hypertens., 2001, vol. 14,
p. 12631269.
PERSELL S.D., Prevalence of resistant hypertension in the United States, 20032008. Hypertension, 2011, vol. 57, p. 1076.
MUXFELDT E.S., NOGUEIRA ADA R., SALLES G.F., BLOCH K.V., Demographic and clinical characteristics of
hypertensive patients in the internal medicine outpatient clinic of a university hospital in Rio de Janeiro. Sao Paulo Med. J.,
2004, vol. 122, no.3, p. 87.
SARAFIDIS P.A., BAKRIS G.L., Resistant hypertension: an overview of evaluation and treatment. J. Am. Coll. Cardiol., 2008,
vol. 57, no. 6, p. 174957.
AMAR J., CHAMONTIN B., GENES N., CANTET C., SALVADOR M., CAMBOU J.P., Why is hypertension so frequently
uncontrolled in secondary prevention? J. Hypertens., 2003, vol. 21, no. 3, p. 1199.
PIMENTA E., GADDAM K.K., OPARIL S., ABAN I., HUSAIN S., DELL'ITALIA L.J., CALHOUN D.A., Effects of dietary
sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension, 2009,
vol. 54, no. 3, p. 475.
GRASSI G., FACCHINI A., TREVANO F.Q., DELLORO R., ARENARE F., TANA F., BOLLA G., MONZANI A.,
ROBUSCHI M., MANCIA G., Obstructive sleep apnea dependent and -independent adrenergic activation in obesity.
Hypertension, 2005, vol. 46, p. 321325.
CALHOUN D.A., NISHIZAKA M.K., ZAMAN M.A., THAKKAR R.B., WEISSMANN P., Hyperaldosteronism among black
and white subjects with resistant hypertension. Hypertension, 2002, vol. 40, no. 6, p. 892.
MOSSO L., CARVAJAL C., GONZLEZ A., BARRAZA A., AVILA F., MONTERO J., HUETE A., GEDERLINI A.,
FARDELLA C.E., Primary aldosteronism and hypertensive disease. Hypertension, 2003, vol. 42, p. 161153.
WEINBERGER M.H., FINEBERG N.S., The diagnosis of primary aldosteronism and separation of two major subtypes. Arch.
Intern. Med., 1993, vol. 153, p. 2125.
BLUMENFELD J.D., SEALEY J.E., SCHLUSSEL Y., VAUGHAN E.D. JR., SOS T.A., ATLAS S.A., MLLER F.B.,
ACEVEDO R., ULICK S., LARAGH J.H., Diagnosis and treatment of primary hyperaldosteronism. Ann. Intern. Med., 1994,
vol. 121, 11, p. 877.
APPEL L.J., MOORE T.J., OBARZANEK E., VOLLMER W.M., SVETKEY L.P., SACKS F.M., BRAY G.A., VOGT T.M.,
CUTLER J.A., WINDHAUSER M.M., LIN P.H., KARANJA N., A clinical trial of the effects of dietary patterns on blood
pressure. DASH Collaborative Research Group. N. Engl. J. Med., 1997, vol. 336, p. 11171124.
MANCIA G., DE BACKER G., DOMINICZAK A., CIFKOVA R., FAGARD R., GERMANO G., GRASSI G., HEAGERTY
A.M., KJELDSEN S.E., LAURENT S., NARKIEWICZ K., RUILOPE L., RYNKIEWICZ A., SCHMIEDER R.E., STRUIJKER
BOUDIER H.A., ZANCHETTI A., 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the
Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of
Cardiology (ESC). J. Hypertension, 2007, vol. 25, p. 11051187.
GADDAM K.K., NISHIZAKA M.K., PRATT-UBUNAMA M.N., PIMENTA E., ABAN I., OPARIL S., CALHOUN D.A.,
Resistant hypertension characterized by increased aldosterone levels and persistent intravascular volume expansion. Arch.
Intern. Med., 2008, vol. 168, 9, p. 11591164.
ERNST M.E., CARTER B.L., GOERDT C.J. et al., Comparative antihypertensive effects of hydrochlorothiazide and
chlorthalidone on ambulatory and office blood pressure. Hypertension, 2006, vol. 47, p. 352358.
CHAPMAN N., DOBSON J., WILSON S. et al., Effect of spironolactone on blood pressure in subjects with resistant
hypertension. Hypertension, 2007, vol. 49, p. 839845.
NISHIZAKA M.K., ZAMAN M.A., CALHOUN D.A., Efficacy of low-dose spironolactone in subjects with resistant
hypertension. Am. J. Hypertension, 2003, vol. 16, p. 925930.
TOWNSEND R.R., DIPETTE D.J., GOODMAN R., BLUMFIELD D., CRONIN R., GRADMAN A., KATZ L.A.,
MCCARTHY E.P., SOPKO G., Combined alpha/betablockade versus beta 1-selective blockade in essential hypertension in
black and white patients. Clin. Pharmacol. Ther., 1990, vol. 48, p. 665675.
GOLDSTEIN D.S., Plasma catecholamines and essential hypertension: an analytical review. Hypertension, 1983, vol. 5, p. 8699.
ANDERSON E.A., SINKEY C.A., LAWTON W.J., MARK A.L., Elevated sympathetic nerve activity in borderline hypertensive
humans: evidence from direct intraneural recordings. Hypertension, 1989, vol. 14, p. 177183.
GRIMSON K.S., Total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy in the treatment of
hypertension. Ann. Surg., 1941, vol. 114, p. 753775.
PEET M., WOODS W., BRADEN S., The surgical treatment of hypertension: results in 350 consecutive cases treated by
bilateral supradiaphragmatic splanchnicectomy and lower dorsal sympathetic gangliectomy. Clinical lecture at New York
session. JAMA, 1940, vol. 115, p. 18751885.
GRIMSON K.S., ORGAIN E.S., ANDERSON B., BROOME R.A., LONGINO F.H., Results of treatment of patients with
hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy. Ann.
Surg, 1949, vol. 129, p. 850871.
Symplicity HTN-1 Investigators, Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood
pressure reduction out to 24 months. Hypertension, 2011, vol. 57, p. 911917.
Symplicity HTN-2 Investigators, ESLER M.D., KRUM H., SOBOTKA P.A., SCHLAICH M.P., SCHMIEDER R.E., BHM
M., Renal sympathetic denervation in patients with treatment resistant hypertension (The Symplicity HTN-2 Trial): a randomised
controlled trial. Lancet, 2010, vol. 376, p. 19031909.

18

Elisabeta Bdil et al.

10

32. SCHMIEDER R.E., REDON J., GRASSI G., KJELDSEN S.E., MANCIA G., NARKIEWICZ K., PARATI G., RUILOPE L.,
VAN DE BORNE P., TSIOUFIS C., ESH position paper: renal denervation - an interventional therapy of resistant
hypertension. Journal of Hypertension, 2012, vol. 30 (5): 83741.
33. SHISHEHBOR M.H., BRAVO E.L., NALLY J.V., Renal denervation to treat resistant hypertension: Guarded optimism.
SHISHEHBOR M.H., BRAVO E.L., NALLY J.V., Cleveland Clinic Journal of Medicine, 2012, vol. 79, 7, p. 501510.
34. PAPADEMETRIOU V., DOUMAS M., FASELIS C., TSIOUFIS C., DOUMA S., GKALIAGKOUSI E., ZAMBOULIS C.,
Carotid Baroreceptor Stimulation for the Treatment of Resistant Hypertension. International Journal of Hypertension, 2011, vol.
2011. 964394.
Received January 15, 2013