Article Type : Review Article
Authors : Degirmenci H, Bakirci EM and Hamur H
Keywords : Resistant hypertension; Pseudo resistance, Secondary causes, Treatment
According to the American guideline, the office blood
pressure of 130/80 mmHg and above in patients taking 3 or more antihypertensive
drugs from different classes is uncontrolled resistant hypertension. In
patients using 4 or more different classes of antihypertensive drugs, if the
office blood pressure is below 130/80 mmHg, controlled resistant hypertension
is mentioned. According to the European guideline, resistant hypertension is
defined as an office blood pressure of at least 140 / 90mmHg despite the full
or highest tolerable dose of at least 3 antihypertensive drugs containing
diuretics. The etiology of resistance hypertension is multifactorial.
Successful treatment requires identification and reversal of lifestyle factors
and to exclude the presence of pseudo resistance. Secondary causes should be
treated. Management of resistant hypertension includes maximization of
lifestyle interventions, use of thiazide-like diuretics (chlorthalidone or
indapamide), addition of a mineralocorticoid receptor antagonist
(spironolactone or eplerenone), and, if blood pressure remains elevated,
stepwise addition of a beta blocker (bisoprolol, metoprolol succinate), and, if
blood pressure remains elevated, stepwise addition of a combined alpha-beta
blocker (labetalol, carvedilol), and if blood pressure remains elevated,
stepwise addition of antihypertensive drugs with complementary mechanisms of
action to lower blood pressure. Device-based treatments are not recommended for
routine treatment of hypertension.
Hypertension is the
main risk factor for cardiovascular disease, stroke, and death. According to
the American guideline, the office blood pressure of 130/80 mmHg and above in
patients taking 3 or more antihypertensive drugs from different classes is
uncontrolled resistant hypertension. In patients using 4 or more different
classes of antihypertensive drugs, if the office blood pressure is below 130/80
mmHg, controlled resistant hypertension is mentioned [1]. According to the
European guideline, resistant hypertension is defined as an office blood
pressure of at least 140 / 90mmHg despite the full or highest tolerable dose of
at least 3 antihypertensive drugs containing diuretics [2]. While the
prevalence of resistant hypertension is 1-5% in all hypertensive, it is 11-15%
in reference clinics. Resistant hypertension is one of the leading causes of
morbidity and mortality related to cardiovascular diseases. That's why we wrote
this mini-review called resistant hypertension.
Advanced age, obesity,
black race, excessive dietary sodium intake, high basal blood pressure and
chronic uncontrolled hypertension are among the demographic characteristics of
patients with resistant hypertension. Risk factors contributing to resistant
hypertension include obesity, physical inactivity, a high-sodium, excess
alcohol intake, obstructive sleep apnea, use of cocaine, amphetamines, no
steroidal anti-inflammatory drugs, oral contraceptive hormones, adrenal steroid
hormones, sympathomimetic drugs, progressive renal insufficiency. Common causes
of secondary hypertension include renal parenchymal disease, atherosclerotic
renovascular disease, sleep apnoea, primary hyperaldosteronism, and drug
induced hypertension or alcohol induced hypertension. Uncommon causes of
secondary hypertension include pheochromocytoma, Cushing’s syndrome,
hypothyroidism, hyperthyroidism, aortic coarctation, primary
hyperparathyroidism, acromegaly, fibro muscular dysplasia, and congenital
adrenal hyperplasia [3-5].
Causes of
pseudoresistance include incorrect blood pressure measurement, uncompressed
calcified in elderly patients atherosclerotic arteries (Pseudohypertension),
non-compliance with antihypertensive treatment, suboptimal antihypertensive
treatment, non-compliance with lifestyle changes, non-compliance with diet and
white coat hypertension [1]. These causes should be excluded in order to make a
correct diagnosis of resistant hypertension. In addition, 24-hour blood
pressure monitoring should be done to exclude the white coat effect.
Secondary hypertension is one of the causes of
resistant hypertension. Secondary hypertension should be suspected if there is
new onset or uncontrolled hypertension in adults. There are certain clinical
clues that suggest secondary hypertension. Sudden onset and progressive
hypertension, papillary edema, oliguria, resistant hypertension, onset of
hypertension over the age of 60, recurrent acute pulmonary edema attacks,
faster than expected deterioration of renal functions with angiotensin
converting enzyme or angiotensin receptor blocker, and systolo-diastole in
abdominal renal artery tracing on physical examination. In the presence of
these symptoms and signs, secondary causes of hypertension should be
investigated [6]
Primarily, the white
coat effect, secondary causes and drug incompatibility should be excluded.
Lifestyle interventions such as low sodium diet (<2400 mg/d), >6 hours
uninterrupted sleep, exercise, overall diet patterns, weight loss should be
maximized. Adherence to 3 different classes of antihypertensive drugs ((renin
angiotensin aldesterone system blocker, calcium channel blocker and diuretic)
should be ensured at the maximum tolerated dose. If blood control is not
achieved, an optimal dose of thiazide-like diuretic (chlorthalidone or
indapamide) is started. If blood pressure control cannot be achieved despite
this added treatment, a mineralocorticoid receptor antagonist (eplerenone
50-100mg/day, aldosterone 25-50 mg daily) is started. Sprinolactone has taken
its place in resistant hypertension with the PATHWAY study. This study showed
that sprinolactone showed more significant blood pressure reduction than with
placebo, doxazosin, and bisoprolol. The PATHWAY-2 study also evaluated
bisoprolol or doxazosin modified release as alternatives to spironolactone [7].
If blood pressure control cannot be achieved, a beta blocker (metoprolol
succinate, bisoprolol) can be added if the heart rate is >70. Again, if
blood pressure control is not achieved, combined alpha-beta blocker drugs
(labetalol, carvedilol) are started. If beta-blocker is contraindicated central
alpha agonist medication (clonidine, guanfacine) is considered. If these drugs
are contraindicated, diltiazem is started once a day. If blood pressure is still
not controlled with the above-described measures, the addition of hydralazine (
25 mg three times daily) should be considered and combined with nitrates
(isosorbide mononitrate, 30 mg daily, max dose 90 mg daily) in cases of heart
failure. Lastly, minoxidil (2.5 mg two-three times daily) may be tried if
hydralazine fails. Several studies have investigated devices that reduce
sympathetic nerve activity (carotid body stimulation and renal denervation);
however, these studies have not provided sufficient evidence to recommend the
use of these device in managing resistant hypertension [8].