ISSN 0326-646X





Sumario Vol. 42 - Nº 3 Julio - Septiembre 2013

Resistant Arterial Hypertension

Gabriel Waisman

Servicio de Clínica Médica y de la Sección Hipertensión Arterial.
Hospital Italiano de Buenos Aires.
Gascón 450. (C1181ACH) Ciudad Autónoma de Buenos Aires.
E mail

Recibido el 20-Abril-2013 – ACEPTADO el 02-MAYO-2013,
The author declare not having conflicts of interest.
Rev Fed Arg Cardiol. 2013; 42(3): 170-173

Print version Imprimir sólo la columna central



According to the National Survey of Risk Factors of 2009 [1], in Argentina sedentarism was observed in 54.9% of the population (18-64 years), smoking in 27.1%, hypertension in 34.8%, overweight and obesity in 53.4%, a scant consumption of vegetables and fruits in 37%, diabetes in around 9.6%, hypercholesterolemia in 28%, and a high alcohol consumption (of risk) in 10%.

The NHANES Registry from USA verified between 1999 and 2004 [2], an increase in the incidence and prevalence of hypertension of almost 30%, but with a higher control rate of blood pressure and figures below 140/90 mmHg in 29% of hypertensive patients until 2000, in 36.8% of them until 2004 and 48% in 2011, with a better control adjusted by age.

In most of the clinical studies, to achieve the goal of controlling both systolic and diastolic blood pressure, using more than one drug was necessary in 66% of the patients.

The classical definition of resistant hypertension refers to the clinical form in which it is impossible to decrease blood pressure below 140/90 mmHg, with adhesion to a treatment that includes changes in lifestyle and a combination of at least 3 antihypertensive drugs in proper doses, among them a diuretic agent [3].

Since 2008, the American Heart Association (AHA)[4] also considers as resistant hypertensive patients, those with blood pressure controlled in the office, but thanks to the use of 4 antihypertensive drugs or more.

The prevalence of resistant hypertension is uncertain. It is thought that it is around 10-15%, but it was observed in 20-30% in large clinical trials, in which the goal of diastolic blood pressure <90 mmHg is reached in 90% of the patients, but the goal of systolic blood pressure <140 mmHg is only reached in 60% of the cases (rule 60/90).

In observational studies and in blood pressure control studies of tertiary institutions, it has been determined that the goals are difficult to reach in up to 35-40% of patients, mainly in relation to the control of systolic pressure [4].

In the ALLHAT study [5], during the fourth and the last year of study, an effective control rate of blood pressure was achieved by combinations of drugs just in 66% of the individuals (27% before randomization and 55% at one year of follow-up). When the study ended, 27% of the patients was medicated with 3 drugs or more, without a proper control of their blood pressure.

Potentially associated factors and etiologies
Refractory hypertension relates to the secondary etiology of hypertension in around 10% of the cases. This situation is more prevalent in individuals older than 60 years, in whom sensibility to salt intervenes pathophysiologically, just as decreased renin, characteristic of this age group and frequent medication associations, as non-steroid antiinflammatory (NSAIs), mainly COX1 inhibitors. In these patients, the drugs of choice are calcium channel blockers since they do not interfere at renal level with NSAIs, as diuretics and renin-angiotensin system (RAS) inhibitors do.

In USA, the first cause of refractory hypertension, curable, is alcohol consumption of risk, which in Argentina affects 10% of the population. Not complying with the therapy (pharmacological or not) or using inappropriate posology plans may also condition the development of refractory hypertension.

Faced with the possibility of observing a falsely pathological situation, resistant hypertension should be reevaluated by using ambulatory blood pressure monitoring of 24 hours (ABPM)[6], method that has even been proposed for a new and possible solution for the problem.

The prognosis of resistant hypertension mainly depends on cardiovascular risk factors and the usually associated co-morbidities, such as diabetes, obstructive sleep apnea syndrome and chronic renal failure.

In recent years, investigation studies have been conducted on pharmacogenetic causes and mechanisms to identify genotypes of hypertension resistant to drugs. Risk predictors of resistant hypertension, according to the Framingham study are: age (in relation to systolic blood pressure), the degree of increase of basal blood pressure, excessive ingestion of salt, chronic renal disease, diabetes, left ventricular hypertrophy, the female gender and the black race.

Both the physical examination, as some noninvasive hemodynamic methods, can be useful to identify the underlying hemodynamic mechanisms that lead to hypertension, and to indicate and combine drugs in a rational manner, so as to solve the problem of each particular patient.

Between the causes of resistant hypertension related to the patient, we find a poor compliance with treatment, with 40% of dropping the medication within the first year of pharmacotherapy, which relates to adverse effects, costs, the absence of regular and continuous medical care, an uncomfortable posology plan due to the dose intervals, not understanding the instructions, denial of the disease, not knowing the risks, cognitive deficit, and so on.

Another of the causes of resistant hypertension is linked to the consumption of other drugs by the patient, such as non-steroid antiinflammatory agents and antidepressants, especially in elderly people (venlafaxine, and to a lesser extent, paroxetine and fluoxetine), nasal drops (vasoconstrictor alpha stimulants) in younger individuals, corticosteroids, oral contraceptives, anorexigenic agents, erythropoietin, cyclosporine, cocaine and others.

The conditions associated with greater frequency to resistant hypertension are obesity, smoking, high alcohol consumption (>30 g/day) and an excessive ingestion of sodium. In general, obese patients have sodium excretion alterations, present an increase in the activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system, and usually receive a larger amount of drugs. Beta blockers for instance, are an obstacle for weight loss and cause a greater decrease of cardiac minute volume in a tight relation to weight.

Smoking also produces peripheral vasoconstriction and essentially, increase in blood pressure variability, mainly when beta blockers are used.

Another clinical situation that should be differentiated, although not frequent, is the so-called pseudo-hypertension, which is observed when the patient presents values of blood pressure higher than those to be expected by the damage of the target organ observed. Blood pressure is falsely estimated as high, in regard to control with arterial catheter, due to calcifications in the middle layers of the artery and the lack of humeral circumflex artery collapse when applying extreme pressure when inflating the cuff.

The symptoms of pseudo-hypertension should be suspected in patients with an advanced age with severe hypertension and scant evidence of damage in the target organ. Besides, they usually present symptoms related to hypotension crises. Osler’s maneuver allows detecting these cases during the measurement of blood pressure, when in inflation radial pulse palpation persists after the noise associated to systolic blood pressure disappears.

In pseudo-hypertensive patients, as brachial artery pressure cannot be considered as a parameter of response to treatment, more representative parameters of the central or aortic hemodynamic situation should be taken into account (although there is no evidence about it), such as measurements of pulse wave velocity (central and/or peripheral) or determining volumes hemodynamically.

Other causes for resistant hypertension are related to the physician and are linked to blood pressure measurement mistakes, white coat effect, inappropriate education of the patient, lack of determination to reach a goal, use of erroneous doses or dose intervals and inappropriate combinations of drugs. Pseudo-resistance may be observed by the white coat effect or phenomenon, which may manifest in up to 30% of the cases; it is also a product of using inappropriate cuffs and the administration of drugs at inappropriate doses and combinations. An excess of volume present in resistant hypertension may also be related to the use of thiazide or loop diuretics, or aldosterone receptor blockers.

Advice for therapeutic management
The concept of hemodynamic balance refers to the tissue flow, by a ratio between blood pressure and peripheral resistance. In the initial stages of hypertension, an increase in cardiac output is observed, with a relative increase of peripheral resistance; but in the clinical practice, most of the patients present a decrease in cardiac output and increase of resistance, much more emphasized in late hypertension (25%), with tissue hypoperfusion, although the value of diastolic blood pressure is kept stable.

Thus, the goals of the treatment of hypertension point to a reduction in systemic vascular resistance, maintenance of cardiac output, improvement of arterial elasticity, and mostly, preservation of tissue perfusion. The hemodynamic rationale of the treatment should consider age, severity of blood pressure increase, creatinine value, ventricular geometry and function, renin levels, degree of obesity, etc.

As to the interactions between anti-hypertensive drugs, since 2007, the combination of beta blockers and thiazide diuretics is no longer recommended as a first choice, neither is that of beta and alpha blockers. Since that year, in the international guidelines (ESH/ESC)[7,8], the advised combinations (class IA) are those of thiazide agents with angiotensin II receptor blockers, with calcium antagonists and with angiotensin I converting enzyme inhibitors; beta blockers with calcium antagonists, and the latter with angiotensin receptor blockers and ACEIs.

According to the hemodynamic reasoning[9,10], those patients that present cardiac output increase and decrease of peripheral resistance, benefit with beta blockers, central sympatholytic agents, diuretics and nondihydropyridine calcium blockers (e.g., diltiazem and verapamil), while in those with the contrary profile, dihydropyridine calcium blockers, angiotensin receptor blockers, ACEIs, alpha blockers or direct vasodilators would be indicated (e.g., hydralazine or minoxidil). As to peripheral resistance, classical beta blockers of the first and second generation constitute agents that increase this variable.

The strategy based on the rationale and hemodynamic studies has shown to benefit the population of patients with resistant hypertension[11], and it entails a lower number of drugs and doses used, when compared to the empiric treatment. Besides, it has been proven that such strategy achieves a greater reduction of blood pressure and a greater percentage of controlled patients.

The mechanisms that contribute to the excess of volume in resistant hypertension include volume retention secondary to the treatment with vasodilators, sodium retention secondary to altered pressure-natriuresis relation, and high levels of aldosterone[12]. In the patients with hypertension secondary to primary aldosteronism, using spironolactone significantly reduces blood pressure in a situation of resistant hypertension, although it does it too in resistant hypertension without primary aldosteronism, both systolic and diastolic.

Another potassium-sparing diuretic, amiloride, has also shown similar benefits, mainly when found associated to hydrochlorothiazide. Between thiazides, chorthalidone presents greater advantages related to its circadian rhythm and, thus, to a greater night control of blood pressure[13-14].

The hemodynamic evaluation may be made by invasive and noninvasive methods (cardiography by impedance, pulse wave velocity, etc.), but also through a general physical examination[15]. This may display volume excess (edema, jugular ingurgitation, rales) correctible with diuretics, excess of catecholamines (HR>84 bpm) that may be controlled with beta blockers or nondihydropyridine calcium blockers, or high peripheral vascular resistance (absence of the mentioned signs) that is managed with renin-angiotensin-aldosterone system blockers or vasodilators.

Secondary hypertension as a cause for resistant hypertension[16], may be clinically suspected from interrogation and physical examination. The diagnosis is oriented from the lab tests and confirmed by specific studies. The first cause of secondary hypertension is parenchymatous nephritis, followed by primary aldosteronism, renovascular hypertension, and sleep apnea.

Paroxysms proper of pheochromocytoma may be shown through 24 h ABPM. The latter also allows ruling out pseudo-resistance or “false refractoriness”; mainly in elderly patients with white coat effect.

The white coat phenomenon may be identified by the hyperventilation test (at least 10 cycles)[17], which causes a marked decrease in pressure at 30 seconds (of 18 mmHg of systolic pressure and 11 mmHg of diastolic pressure, at 7 mmHg and 5 mmHg, respectively), in patients without these phenomenon. A significant decrease in systolic blood pressure in the hyperventilation test correlates to the finding of falsely resistant hypertension in 24 h blood measuring. The mechanisms by which an acute drop in blood pressure occurs relate to pulmonary mechanoreceptors, as has been proven in test animals studies.

Likewise, the opposite situation has been described;that of concealed hypertension (inverted white coat)[18], mainly in male smoking patients, particularly young and with type 2 diabetes, who receive antihypertensive treatment.

An algorithm can be followed to manage resistant hypertension or hypertension difficult to manage[19]. Once diagnosed, pseudo-hypertension and white coat phenomenon should be ruled out; later, the patient’s compliance should be reevaluated, as well as adverse effects and/or economic or cultural aspects, substances and drugs that may interfere with pharmacotherapy and the doses are suspended or reduced, maximizing the indication of antihypertensive drugs. In obese patients, it is necessary to guarantee a proper measurement of blood pressure and making indications about lifestyle changes. After all these steps, all possible secondary causes of hypertension should be diagnosed and treated, and the pharmacological treatment should be optimized and intensified. In the therapeutic algorithm, the first step before resistant hypertension is restricting salt and adjusting diuretics to renal function, using loop diuretics with creatinine >1.5 and glomerular filtration <30 ml/minute. In the case of resistance persisting, it is advised to add a new kind of drug, taking into account the hemodynamic situation of the patient. The patient may have to be referred to a specialized center, with therapeutic tests with spironolactone[20], or treatment guided by the hemodynamic characteristics. As additional therapy, drugs with alpha and beta blocking action, dual calcium blockers, combinations of the renin-angiotensin-aldosterone system blockers, agents of central action or direct vasodilators, such as hydralazine and minoxidil can be used (always accompanied by beta blockers and diuretics).



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Publication: September 2013

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