7th Brazilian Guideline of Arterial Hypertension: Chapter 13 - Resistant Arterial Hypertension

 [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large,..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Apparent and true resistant hypertension: definition, prevalence and outcomes, Judd [/bib_ref] [bib_ref] Measuring, analyzing, and managing drug adherence in resistant hypertension, Burnier [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] 

## Complementary tests
Blood biochemistry, urinalysis and ECG should be requested at the time of diagnosis, and repeated at least once a year. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] Echocardiogram and retinal exam, when available, should be repeated every 2 to 3 years.

## Secondary causes
Secondary causes are common in RAH, 6 OSAHS being the most prevalent (80%, and 50% with moderate-severe apnea), [bib_ref] Prevalence and associated factors of obstructive sleep apnea in patients with resistant..., Muxfeldt [/bib_ref] followed by hyperaldosteronism (20%, mainly adrenal hyperplasia) [bib_ref] Hyperaldosteronism as a common cause of resistant hypertension, Calhoun [/bib_ref] and renal artery stenosis (2.5%). Other secondary causes should only be investigated in the presence of suggestive clinical findings. 6

## Abpm and hbpm
Although the diagnosis of RAH is based on office BP measurement, 1 BP assessment by using ABPM or HBPM is mandatory for the initial diagnosis and clinical follow-up. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Is home blood pressure monitoring useful in the management of patients with..., Muxfeldt [/bib_ref] It is estimated that 30-50% of resistant hypertensive individuals have normal outside-the-office BP levels. 9,12,16 The diagnosis obtained on ABPM defines diagnostic and therapeutic management (Chart 1). [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] In true or masked RAH, the medication should be progressively adjustedwith the introduction of nocturnal doses of antihypertensive drugs. [bib_ref] Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients..., Hermida [/bib_ref] Patients with controlled BP on ABPM should have their therapy maintained, regardless of the office BP levels. In white-coat RAH, confirmatory ABPM needs to be performed after 3 months, and repeated every six months (if wakefulness SBP  115 mm Hg) or annually (if wakefulness SBP < 115 mm Hg). [bib_ref] Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with..., Muxfeldt [/bib_ref] When ABPM is not available, HBPM is a good complementary method. Although it does not assess the nocturnal period and overestimates BP levels, HBPM reaches moderate agreement on the diagnosis, [bib_ref] Home versus ambulatory blood pressure monitoring in the diagnosis of clinic resistant..., Nasothimiou [/bib_ref] with high specificity and low sensitivity (Chart 2). 17

## Treatment non-pharmacological treatment
The NPT is aimed at:
Encouraging lifestyle changes: reduction in salt intake (up to 2.0 g of sodium/day); DASH diet; body weight loss (BMI < 25 kg/m 2 ); physical activity; smoking cessation; and moderate alcohol intake; [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] First Brazilian position on resistant hypertension, Alessi [/bib_ref] [bib_ref] Effects of dietary sodium reduction on blood pressure in subjects with resistant..., Pimenta [/bib_ref] [bib_ref] Heated water-based exercise training reduces 24-hour ambulatory blood pressure levels in resistant..., Guimaraes [/bib_ref] Suspending substances that raise BP. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] 

## Pharmacological treatment
The basic principle of the pharmacological treatment is the association of antihypertensive drugs that block most pathophysiological mechanisms of BP elevation. Ideally, the following should be prescribed at full-tolerated dose and at proper intervals: a DIU, a RAAS inhibitor, and a dihydropyridine CCB. In certain situations, such as CAD, CHF and tachyarrhythmias, a BB can replace a CCB in the initial therapeutic regimen with 3 medications.
The correct use of DIUs to ensure control of volemic expansion is essential, and more than half of the patients can meet the BP target with DIU optimization. [bib_ref] Resistant hypertension revisited: a comparison of two university based cohorts, Garg [/bib_ref] Chlorthalidone is superior to hydrochlorothiazide. [bib_ref] Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood..., Ernst [/bib_ref] For stage 4 or 5 CKD patients, loop DIUs should be used and administered at least twice a day. Spironolactone, an aldosterone antagonist, is the choice for the fourth drug in patients with true RAH, enabling a mean reduction of 15-20 mm Hg in SBP, and of 7-10 mm Hg in DBP, at doses of 25-50 mg/day. [bib_ref] Effect of aldosterone antagonists on blood pressure in patients with resistant hypertension:..., Liu [/bib_ref] However, up to 20-30% of the patients might not tolerate its use, because of renal function worsening, hyperpotassemia, gynecomastia or mastalgia. In such cases, amiloride can be used (5-10 mg/ day), but with an apparently lower BP response. [bib_ref] Amiloride 10 mg is less effective than spironolactone 25 mg in patients..., Lane [/bib_ref] The use of clonidine as the fourth drug is being assessed in the Brazilian ReHOT study, considering the sympathetic and RAAS activity measurements as possible predictors of the best therapeutic response to clonidine and spironolactone, respectively. [bib_ref] ReHOT Investigators. Resistant hypertension optimal treatment trial: a randomized controlled trial, Krieger [/bib_ref] In patients not reaching BP control on ABPM after the addition of spironolactone, BBs (mainly those with vasodilating effect) are the fifth drugs, if not contraindicated. Central alpha-agonists (clonidine and alpha methyldopa), direct vasodilators (hydralazine and minoxidil), or central agonists of imidazoline receptors are usually used as the sixth and seventh drugs. In addition, associations of multiple DIUs (thiazide DIUs, loop DIUs and spironolactone), especially in the presence of edema, or dihydropyridine and non-dihydropyridine CCBs can be used in the most critically ill patients.
Chronotherapy guided by ABPM, with the nocturnal administration of at least one antihypertensive drug, could improve BP control and reverse the unfavorable nondipping pattern in those patients, in addition to reducing CV morbidity and mortality (Chart 3). [bib_ref] Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients..., Hermida [/bib_ref] 

## New therapeutic strategies
New strategies are being developed, but are still experimental. Although safe, they are not better than the conventional treatment, and should only be used in truly resistant patients (Chart 4).

## Direct and chronic stimulation of carotid sinus baroreceptors
The Rheos system is a programable device, like a pacemaker, surgically implanted, consisting in a generator of impulses that activate the carotid baroreceptors via radiofrequency. The Rheos Pivotal Trial has not detected significant long-term benefits. [bib_ref] Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results..., Bakris [/bib_ref] 

## Renal sympathetic denervation
Percutaneous transluminal renal sympathetic denervation through a catheter has been mainly assessed in the SYMPLICITY studies conducted in RAH patients. Recent meta-analyses [bib_ref] Metaanalysis of five prospective and randomized trials of renal sympathetic denervation on..., Elmula [/bib_ref] have not confirmed the initially promising results.

## Use of cpap
The antihypertensive effect of CPAP is controversial. However, as an auxiliary treatment in patients with OSAHS, mainly those who tolerate its use for more than 4 hours/ night, there is evidence that it can help to reestablish the dipping pattern. 29

## Chart 2 -diagnostic investigation of rah

## Central iliac arteriovenous anastomosis
The ROX Control HTN study 30 has shown promising results with significant reductions in BP levels and in hypertensive complications of patients with central iliac arteriovenous anastomosis with the coupler device.

## Prognosis
A retrospective cohort study performed from a North American registry indicates that, after beginning the antihypertensive treatment, the apparent RAH incidence (uncontrolled BP with 3 medications) is 0.7/100/patients-year, and those patients' relative risk for CV events is 1.47 (95% confidence interval: 1.33-1.62). [bib_ref] Incidence and prognosis of resistant hypertension in hypertensive patients, Daugherty [/bib_ref] A prospective study with 556 resistant hypertensives (follow-up of 4.8 years) has shown that uncontrolled ABPM and lack of nocturnal dipping are important markers of CV risk. [bib_ref] Prognostic factors in resistant hypertension: implications for cardiovascular risk stratification and therapeutic..., De Souza [/bib_ref] The apparent RAH condition is considered of independent risk for the occurrence of CV events. (GR: IIa; LE: C). Performing ABPM is recommended to establish the prognosis of hypertensives with true RAH. (GR: IIa; LE: C). Central arteriovenous anastomosis (coupler device)IIb B
[table] , 3: Chart 1 -Classification of RAH based on ABPM [/table]