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

Resistant AH (RAH) is defined as uncontrolled office BP despite the use of at least three antihypertensive drugs at appropriate doses, including preferably one DIU, or as controlled BP using at least four drugs.1-3 Because it does not include the systematic assessment of therapy and adherence, that situation is better defined as apparent RAH (pseudoresistance). Identification of true RAH is fundamental to establish specific approaches.2 Population-based studies have estimated a 12% prevalence in the hypertensive population.2 In Brazil, the ReHOT study assesses prevalence and therapeutic choice.4 Refractory hypertension is defined as uncontrolled BP using at least five antihypertensive drugs,5 and corresponds to 3.6% of resistant hypertensive individuals. To diagnose RAH, ABPM is required, as well as systematic assessment of adherence. (GR: I; LE: C).

The pathophysiological aspects related to resistance are as follows: (i) sympathetic and RAAS hyperactivity; (ii) vascular smooth muscle proliferation; (iii) sodium retention; and (iv) activation of proinflammatory factors. 1,7 Greater endothelial dysfunction and arterial stiffness are present. 8 In ABPM, there is high prevalence (30%) of WCE and attenuation of nocturnal BP dipping. 9 The prevalence of black ethnicity, DM and albuminuria is higher among refractory hypertensive individuals. 5 Diagnostic investigation Pseudoresistance Pseudoresistance is due to poor BP measurement technique, low adherence to treatment and inappropriate therapeutic regimen. 1,2,10 Studies have shown that 50-80% of the patients fail to adhere to treatment completely or partially. [10][11][12] The diagnosis of RAH should only be established after inclusion of an appropriate DIU 13 and adjustment of the antihypertensive regimen. 12

Complementary tests
Blood biochemistry, urinalysis and ECG should be requested at the time of diagnosis, and repeated at least once a year. 1,12 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), 14 followed by hyperaldosteronism (20%, mainly adrenal hyperplasia) 15 and renal artery stenosis (2.5%). 6 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. 1,9,16,17 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). 1,12,16 In true or masked RAH, the medication should be progressively adjusted 16 with the introduction of nocturnal doses of antihypertensive drugs. 18 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). 19 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, 20 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; 1,3,21,22 Suspending substances that raise BP. 1

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. 13 Chlorthalidone is superior to hydrochlorothiazide. 23 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. 24 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. 25 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. 4 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). 18

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. 26

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 27,28 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

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). 31 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. 32 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) 30 IIb B