Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC gLk9Tt7XP48945CVpKYXMkQ S0066-782X2016004800075 10.5935/abc.20160163 Diretrizes 7th Brazilian Guideline of Arterial Hypertension: Chapter 13 - Resistant Arterial Hypertension Malachias MVB Rodrigues CIS Muxfeldt E Salles GF Moreno H Júnior Gus M 09 2016 107 3 Suppl 3 75 78 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Definition and epidemiology

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).

 Associated factors

Causative factors are as follows: higher salt sensitivity, increased blood volume (higher sodium intake, CKD or inappropriate diuretic therapy), exogenous substances that raise BP, and secondary causes (OSAHS, primary aldosteronism, CKD, and renal artery stenosis).1,3,6 The characteristics of RAH are: more advanced age, African ancestry, obesity, MS, DM, sedentary lifestyle, chronic nephropathy, and LVH.1,3

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.10-12 The diagnosis of RAH should only be established after inclusion of an appropriate DIU13 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

Major causes of secondary AH, signs and diagnostic screening
Clinical findings Diagnostic suspicion Additional studies
Snoring, daytime sleepiness, MS OSAHS Berlin questionnaire, polysomnography or home respiratory polygraphy with at least 5 episodes of apnea and/or hypopnea per sleep hour
RAH and/or hypopotassemia (not necessary) and/or adrenal nodule Primary hyperaldosteronism (adrenal hyperplasia or adenoma) Measurements of Aldo (>15 ng/dL) and plasma renin activity/concentration; Aldo/renin > 30. Confirmatory tests (furosemide and captopril). Imaging tests: thinsliced CT or MRI
Edema, anorexia, fatigue, high creatinine and urea, urine sediment changes Parenchymal kidney disease Urinalysis, GFR calculation, renal US, search for albuminuria/proteinuria
Abdominal murmur, sudden APE, renal function changes due to drugs that block the RAAS Renovascular disease Renal Doppler US and/or renogram, angiography via MRI or CT, renal arteriography
Absent or decreased femoral pulses, decreased BP in the lower limbs, chest X ray changes Coarctation of the aorta Echocardiogram and/or chest angiography via CT
Weight gain, decreased libido, fatigue, hirsutism, amenorrhea, moon face, “buffalo hump”, purple striae, central obesity, hypopotassemia Cushing’s syndrome (hyperplasia, adenoma and excessive production of ACTH) Salivary cortisol, 24-h urine free cortisol and suppression test: morning cortisol (8h) and 8 hours after administration of dexamethasone (1 mg) at 24h. MRI
Paroxysmal AH with headache, sweating and palpitations Pheochromocytoma Free plasma metanephrines, plasma catecholamines and urine metanephrines. CT and MRI
Fatigue, weight gain, hair loss, DAH, muscle weakness Hypothyroidism TSH and free T4
Increased sensitivity to heat, weight loss, palpitations, exophthalmos, hyperthermia, hyperreflexia, tremors, tachycardia Hyperthyroidism TSH and free T4
Renal lithiasis, osteoporosis, depression, lethargy, muscle weakness or spasms, thirst, polyuria Hyperparathyroidism (hyperplasia or adenoma) Plasma calcium and PTH
Headache, fatigue, visual disorders, enlarged hands, feet and tongue Acromegaly Baseline IGF-1 and GH and during oral glucose tolerance test

OSAHS: obstructive sleep apnea-hypopnea syndrome; Aldo: aldosterone; RAH: resistant arterial hypertension; GFR: glomerular filtration ratio; APE: acute pulmonary edema; RAAS: renin-angiotensin-aldosterone system; CT: computed tomography; ACTH: adrenocorticotropin; TSH: thyroid stimulating hormone; PTH: parathormone; IGF-1: insulin-like growth factor type 1; GH: growth hormone.

In true or masked RAH, the medication should be progressively adjusted16 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

ACC/AHA recommendations for renal artery stenosis search during coronary angiography
Clinical characteristics Level of evidence
Beginning of hypertension < 30 years B
Beginning of severe hypertension > 55 years B
Accelerated/malignant hypertension C
Resistant hypertension C
Uremia or renal function worsening after use of ACEI or ARB (> 30% drop in glomerular filtration) B
Atrophic kidney of unknown cause or size discrepancy between the two kidneys > 1.5 cm B
Unexpected sudden pulmonary edema (mainly in uremic patients) B
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/m2); physical activity; smoking cessation; and moderate alcohol intake;1,3,21,22

Suspending substances that raise BP.1,3

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 non-dipping pattern in those patients, in addition to reducing CV morbidity and mortality (Chart 3).18

Clinical indicators of probable renovascular hypertension
Probability Clinical characteristics
Low (0.2%) Uncomplicated borderline or mild/moderate AH
Intermediate (5-15%) Severe or resistant AH Recent AH < 30 years or > 50 years Presence of abdominal murmur Asymmetry of radial or carotid pulses Moderate AH associated with smoking or atherosclerosis in another site (coronary or carotid) Undefined renal functional deficit Exaggerated BP response to ACEIs
High (25%) Severe or resistant AH with progressive renal failure Accelerated or malignant AH Sudden APE ACEI-induced creatinine increase Asymmetry of renal size or function
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).

Medicines and illicit and licit drugs related to AH development or worsening
Drug class Effect on BP and frequency Suggested action
Immunosuppressants Cyclosporine, tacrolimus Intense and frequent ACEI and CCB (nifedipine/amlodipine). Adjust serum level. Reassess options
Anti-inflammatory agents Glucocorticoid Variable and frequent
Non-steroids (1 and 2 cyclo-oxygenase inhibitors) Occasional, very relevant with continuous use Salt restriction, DIUs, decrease dose Observe renal function, use for a short period
Anorexigenic/satiety drugs Diethylpropion and others Intense and frequent Suspension or dose reduction
Sibutramine Intermediate, little relevance Assess BP reduction with weight loss
Vasoconstrictors, including ergot derivatives Variable, transient Use for a determined short period
Hormones Human erythropoietin Variable and frequent Assess hematocrit and dose weekly
Oral contraceptives Variable, prevalence of up to 5% Assess method replacement with an expert
Estrogen-replacement therapy (conjugated estrogens and estradiol) Variable Assess risk and cost-benefit
GH (adults) Variable, dose-dependent Suspension
Antidepressant drugs Monoamine-oxidase inhibitors Intense, infrequent Approach as adrenergic crisis
Tricyclics Variable and frequent Approach as adrenergic crisis
Illicit drugs and alcohol Amphetamine, cocaine and derivatives Acute, intense effect Dose-dependent Approach as adrenergic crisis
Alcohol Variable and dose-dependent Very prevalent See non-pharmacological treatment
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-analyses27,28 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 study30 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).

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First Brazilian position on resistant hypertension. Arq Bras Cardiol. 2012;99(1):576-85. Erratum in: Arq Bras Cardiol. 2013;100(3):304. Alessi A Brandão AA Coca A Cordeiro AC Nogueira AR Diógenes de Magalhães F First Brazilian position on resistant hypertension nullErratum in Arq Bras Cardiol. 2013;100(3):304 Arq Bras Cardiol 2012 99 1 576 585 4 Krieger EM, Drager LF, Giorgi DM, Krieger JE, Pereira AC, Barreto-Filho JA, et al; ReHOT Investigators. Resistant hypertension optimal treatment trial: a randomized controlled trial. Clin Cardiol. 2014;37(1):1-6. Erratum in: Clin Cardiol. 2014;37(6):388. Krieger EM Drager LF Giorgi DM Krieger JE Pereira AC Barreto-Filho JA ReHOT Investigators Resistant hypertension optimal treatment trial: a randomized controlled trial nullErratum in Clin Cardiol. 2014;37(6):388 Clin Cardiol 2014 37 1 1 6 5 Calhoun DA, Booth JN 3rd, Oparil S, Irvin MR, Shimbo D, Lackland DT, et al. Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension. 2014;63(3):451-8. Calhoun DA Booth JN 3rd Oparil S Irvin MR Shimbo D Lackland DT Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort Hypertension 2014 63 3 451 458 6 Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58(5):811-7. Pedrosa RP Drager LF Gonzaga CC Sousa MG de Paula LK Amaro AC Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension Hypertension 2011 58 5 811 817 7 de Faria AP, Modolo R, Fontana V, Moreno H. Adipokines: novel players in resistant hypertension. J Clin Hypertens (Greenwich). 2014;16(10):754-9. de Faria AP Modolo R Fontana V Moreno H Adipokines; novel players in resistant hypertension J Clin Hypertens (Greenwich) 2014 16 10 754 759 8 Figueiredo VN, Yugar-Toledo JC, Martins LC, Martins LB, de Faria AP, de Haro Moraes C, et al. Vascular stiffness and endothelial dysfunction: correlations at different levels of blood pressure. Blood Press. 2012;21(1):31-8. Figueiredo VN Yugar-Toledo JC Martins LC Martins LB de Faria AP de Haro Moraes C Vascular stiffness and endothelial dysfunction: correlations at different levels of blood pressure Blood Press 2012 21 1 31 38 9 de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57(5):898-902. de la Sierra A Segura J Banegas JR Gorostidi M de la Cruz JJ Armario P Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring Hypertension 2011 57 5 898 902 10 Egan BM, Zhao Y, Li J, Brzezinski WA, Todoran TM, Brook RD, et al. Prevalence of optimal treatment regimens in patients with apparent treatment-resistant hypertension based on office blood pressure in a community-based practice network. Hypertension. 2013;62(4):691-7. Egan BM Zhao Y Li J Brzezinski WA Todoran TM Brook RD Prevalence of optimal treatment regimens in patients with apparent treatment-resistant hypertension based on office blood pressure in a community-based practice network Hypertension 2013 62 4 691 697 11 Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension. 2013;62(2):218-25. Burnier M Wuerzner G Struijker-Boudier H Urquhart J Measuring, analyzing, and managing drug adherence in resistant hypertension Hypertension 2013 62 2 218 225 12 Muxfeldt ES, de Souza F, Salles GF. Resistant hypertension: a practical clinical approach. J Hum Hypertens. 2013;27(11):657-62. Muxfeldt ES de Souza F Salles GF Resistant hypertension: a practical clinical approach J Hum Hypertens 2013 27 11 657 662 13 Garg JP, Elliott WJ, Folker A, Izhar M, Black HR; RUSH University Hypertension Service. Resistant hypertension revisited: a comparison of two university based cohorts. Am J Hypertens. 2005;18(5 Pt 1):619-26. Garg JP Elliott WJ Folker A Izhar M Black HR RUSH University Hypertension Service Resistant hypertension revisited: a comparison of two university based cohorts Am J Hypertens 2005 18 5 Pt 1 619 626 14 Muxfeldt ES, Margallo VS, Guimarães GM, Salles GF. Prevalence and associated factors of obstructive sleep apnea in patients with resistant hypertension. Am J Hypertens. 2014;27(8):1069-78. Muxfeldt ES Margallo VS Guimarães GM Salles GF Prevalence and associated factors of obstructive sleep apnea in patients with resistant hypertension Am J Hypertens 2014 27 8 1069 1078 15 Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med. 2013;64:233-47. Calhoun DA Hyperaldosteronism as a common cause of resistant hypertension Annu Rev Med 2013 64 233 247 16 Muxfeldt ES; Salles GF. How to use ambulatory blood pressure monitoring in resistant hypertension. Hypertens Res. 2013;36(5):385-9. Muxfeldt ES Salles GF How to use ambulatory blood pressure monitoring in resistant hypertension Hypertens Res 2013 36 5 385 389 17 Muxfeldt ES, Barros GS, Viegas BB, Carlos FO, Salles GF. Is home blood pressure monitoring useful in the management of patients with resistant hypertension? Am J Hypertens. 2015;28(2):190-9. Muxfeldt ES Barros GS Viegas BB Carlos FO Salles GF Is home blood pressure monitoring useful in the management of patients with resistant hypertension Am J Hypertens 2015 28 2 190 199 18 Hermida RC, Ayala DE, Fernández JR, Calvo C. Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients with resistant hypertension. Hypertension. 2008;51(1):69-76. Hermida RC Ayala DE Fernández JR Calvo C Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients with resistant hypertension Hypertension 2008 51 1 69 76 19 Muxfeldt ES, Fiszman R, de Souza F, Viegas B, Oliveira FC, Salles GF. Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with white-coat resistant hypertension. Hypertension. 2012;59(2):384-9. Muxfeldt ES Fiszman R de Souza F Viegas B Oliveira FC Salles GF Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with white-coat resistant hypertension Hypertension 2012 59 2 384 389 20 Nasothimiou EG, Tzamouranis D, Roussias LG, Stergiou GS. Home versus ambulatory blood pressure monitoring in the diagnosis of clinic resistant and true resistant hypertension. J Hum Hypertens. 2012;26(12):696-700. Nasothimiou EG Tzamouranis D Roussias LG Stergiou GS Home versus ambulatory blood pressure monitoring in the diagnosis of clinic resistant and true resistant hypertension J Hum Hypertens 2012 26 12 696 700 21 Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell'Italia LJ, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension. 2009;54(3):475-81. Pimenta E Gaddam KK Oparil S Aban I Husain S Dell'Italia LJ Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial Hypertension 2009 54 3 475 481 22 Guimaraes GV, de Barros Cruz LG, Fernandes-Silva MM, Dorea EL, Bocchi EA. Heated water-based exercise training reduces 24-hour ambulatory blood pressure levels in resistant hypertensive patients: a randomized controlled trial (HEx trial). Int J Cardiol. 2014;172(2):434-41. Guimaraes GV de Barros Cruz LG Fernandes-Silva MM Dorea EL Bocchi EA Heated water-based exercise training reduces 24-hour ambulatory blood pressure levels in resistant hypertensive patients: a randomized controlled trial (HEx trial) Int J Cardiol 2014 172 2 434 441 23 Ernst ME, Carter BL, Zheng S, Grimm RH Jr. Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J Hypertens. 2010;23(4):440-6. Ernst ME Carter BL Zheng S Grimm RH Jr Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium Am J Hypertens 2010 23 4 440 446 24 Liu G, Zheng XX, Xu YL, Lu J, Hui RT, Huang XH. Effect of aldosterone antagonists on blood pressure in patients with resistant hypertension: a meta-analysis. J Hum Hypertens. 2015;29(3):159-66. Liu G Zheng XX Xu YL Lu J Hui RT Huang XH Effect of aldosterone antagonists on blood pressure in patients with resistant hypertension: a meta-analysis J Hum Hypertens 2015 29 3 159 166 25 Lane DA, Beevers DG. Amiloride 10 mg is less effective than spironolactone 25 mg in patients with hypertension resistant to a multidrug regime including an angiotensin-blocking agent. J Hypertens. 2007;25(12):2515-6. Lane DA Beevers DG Amiloride 10 mg is less effective than spironolactone 25 mg in patients with hypertension resistant to a multidrug regime including an angiotensin-blocking agent J Hypertens 2007 25 12 2515 2516 26 Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens. 2012;6(2):152-8. Bakris GL Nadim MK Haller H Lovett EG Schafer JE Bisognano JD Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial J Am Soc Hypertens 2012 6 2 152 158 27 Fadl Elmula F, Jin Y, Larstorp AC, Persu A, Kjeldsen SE, Staessen JA. Meta-analysis of five prospective and randomized trials of renal sympathetic denervation on office and ambulatory systolic blood pressure in treatment resistant hypertension. J Hypertens. 2015;33 Suppl1:e107. Fadl Elmula F Jin Y Larstorp AC Persu A Kjeldsen SE Staessen JA Meta-analysis of five prospective and randomized trials of renal sympathetic denervation on office and ambulatory systolic blood pressure in treatment resistant hypertension J Hypertens 2015 33 1 e107 28 Fadl Elmula FE, Jin Y, Yang WY, Thijs L, Lu YC, Larstorp AC, et al; European Network Coordinating Research On Renal Denervation (ENCOReD) Consortium. Meta-analysis of randomized controlled trials on renal denervation in treatment -resistant hypertension. Blood Press. 2015;24(5):263-74. Fadl Elmula FE Jin Y Yang WY Thijs L Lu YC Larstorp AC European Network Coordinating Research On Renal Denervation Consortium Meta-analysis of randomized controlled trials on renal denervation in treatment -resistant hypertension Blood Press 2015 24 5 263 274 29 Martinez-Garcia MA, Capote F, Campos-Rodriguez F, Lloberes P, Díaz de Atauri MJ, Somoza M, et al; Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 2013;310(22):2407-15. Martinez-Garcia MA Capote F Campos-Rodriguez F Lloberes P Díaz de Atauri MJ Somoza M Spanish Sleep Network Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial JAMA 2013 310 22 2407 2415 30 Lobo MD, Sobotka PA, Stanton A, Cockcroft JR, Sulke N, Dolan E, et al; ROX CONTROL HTN Investigators. Central arteriouvenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN Study): a randomised controlled trial. Lancet. 2015;385(9978):1634-41. Lobo MD Sobotka PA Stanton A Cockcroft JR Sulke N Dolan E ROX CONTROL HTN Investigators Central arteriouvenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN Study): a randomised controlled trial Lancet 2015 385 9978 1634 1641 31 Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635-42. Daugherty SL Powers JD Magid DJ Tavel HM Masoudi FA Margolis KL Incidence and prognosis of resistant hypertension in hypertensive patients Circulation 2012 125 13 1635 1642 32 de Souza F, Muxfeldt ES, Salles GF. Prognostic factors in resistant hypertension: implications for cardiovascular risk stratification and therapeutic management. Expert Rev Cardiovasc Ther. 2012;10(6):735-45. de Souza F Muxfeldt ES Salles GF Prognostic factors in resistant hypertension: implications for cardiovascular risk stratification and therapeutic management Expert Rev Cardiovasc Ther 2012 10 6 735 745 7ª Diretriz Brasileira de Hipertensão Arterial: Capítulo 13 - Hipertensão Arterial Resistente Malachias MVB Rodrigues CIS Muxfeldt E Salles GF Moreno H Júnior Gus M Definição e epidemiologia

A hipertensão arterial resistente (HAR) é definida como a PA de consultório não controlada apesar do uso de três ou mais anti-hipertensivos em doses adequadas, incluindo-se preferencialmente um DIU, ou em uso de quatro ou mais medicamentos com controle pressórico.1-3 Por não incluir a verificação sistemática da terapêutica e da adesão, essa situação é melhor definida como HAR aparente (pseudorresistência). A identificação da HAR verdadeira é fundamental para estabelecer abordagens específicas.2 Estudos populacionais estimam prevalência em 12% da população hipertensa.2 No Brasil, o estudo ReHOT está avaliando a prevalência e escolha terapêutica.4 A hipertensão refratária é definida como a PA não controlada sob o uso de cinco ou mais anti-hipertensivos,5 e corresponde a 3,6% dos hipertensos resistentes. Para o diagnóstico de HAR é necessária medida ambulatorial de PA e verificação sistemática de adesão. (GR: I; NE: C).

 Fatores associados

Os fatores causais incluem maior sensibilidade ao sal, volemia aumentada (maior ingestão de sódio, DRC ou inadequada terapêutica diurética), substâncias exógenas que elevam a PA e causas secundárias (SAHOS, aldosteronismo primário, DRC e estenose de artéria renal).1,3,6 São características da HAR: idade mais avançada, afro-descendência, obesidade, SM, DM, sedentarismo, nefropatia crônica e HVE.1,3

Os aspectos fisiopatológicos relacionados à resistência incluem: (i) hiperativação simpática e do SRAA, (ii) proliferação da musculatura lisa vascular, (iii) retenção de sódio e (iv) ativação de fatores pró-inflamatórios.1,7 Maior disfunção endotelial e rigidez arterial estão presentes.8 Na MAPA, há alta prevalência (30%) do EAB e atenuação do descenso noturno.9 Os hipertensos refratários têm maior prevalência de raça negra, DM e albuminúria.5

Investigação diagnóstica Pseudorresistência

A pseudorresistência deve-se à má técnica de medição da PA, má adesão e/ou esquema terapêutico inadequado.1,2,10 Estudos mostraram que 50-80% dos pacientes não aderem à medicação total ou parcialmente.10-12 O diagnóstico de HAR deve ser feito somente após a inclusão de um DIU apropriado13 e o ajuste do esquema anti-hipertensivo.12

Exames complementares

Bioquímica sanguínea, avaliação urinária e ECG devem ser solicitados no momento do diagnóstico e repetidos pelo menos anualmente.1,12 Ecocardiograma e fundoscopia, quando disponíveis, devem ser repetidos a cada 2 ou 3 anos.

 Causas secundárias

As causas secundárias são comuns na HAR,6 sendo a mais prevalente a SAHOS (80%, sendo 50% com apneia moderada-grave),14 seguida do hiperaldosteronismo (20%, principalmente hiperplasia adrenal)15 e da estenose de artéria renal (2,5%).6 Outras causas secundárias devem ser investigadas apenas quando o quadro clínico for sugestivo.6

MAPA e MRPA

Apesar do diagnóstico da HAR ser baseado na PA de consultório,1 a avaliação da PA através da MAPA ou da MRPA é mandatória no diagnóstico inicial e no acompanhamento clínico.1,9,16,17 Estima-se que 30-50% dos hipertensos resistentes apresentem níveis tensionais normais fora do consultório.9,12,16 O diagnóstico obtido na MAPA irá definir a conduta diagnóstica e terapêutica (Quadro 1).1,12,16

Classificação de HAR de acordo com a MAPA
PA de consultório MAPA
PA vigília ≥ 135/85 e/ou PA sono ≥ 120/70 mmHg PA vigília < 135/85 e PA sono < 120/70 mmHg
≥ 140/90 mmHg HAR verdadeira HAR do avental branco
< 140/90 mmHg HAR mascarada HAR controlada

Na HAR verdadeira ou mascarada a medicação deve ser progressivamente ajustada16 com introdução de doses noturnas de anti-hipertensivos.18 Pacientes com PA controlada na MAPA devem ter sua terapia mantida, independente dos valores da PA de consultório. Na HAR do avental branco, a MAPA confirmatória precisa ser realizada depois de 3 meses e repetida semestralmente (se PAS vigília ≥ 115 mmHg) ou anualmente (se PAS de vigília < 115 mmHg).19

A MRPA é bom método complementar quando não se dispõe da MAPA. Apesar de não avaliar o período noturno e superestimar os níveis pressóricos, apresenta uma concordância moderada no diagnóstico,20 com alta especificidade e baixa sensibilidade (Quadro 2).17

Investigação diagnóstica na HAR
Grau de recomendação Nível de evidência
Afastar pseudorresistência
Adesão à terapêutica I C
Ajuste do esquema anti-hipertensivo I C
Exames complementares
Bioquímica de sangue: glicose, creatinina, potássio e lipidograma Avaliação urinária: albuminúria e proteinúria ECG I C
Investigação de causas secundárias
SAHOS Hiperaldosteronismo Estenose de artéria renal I A
MAPA ou MRPA
Avaliação do controle pressórico IIa C
Tratamento Tratamento não medicamentoso

- Incentivar MEV: redução da ingesta de sal (até 2,0 g de sódio/dia); dieta DASH; perda de peso (IMC <25 kg/m2) ; atividade física; interrupção do tabagismo e consumo moderado de álcool.1,3,21,22

- Interromper substâncias que aumentam a PA.1,3

Tratamento medicamentoso

O princípio básico é a associação de anti-hipertensivos que bloqueiem a maioria dos mecanismos fisiopatológicos de elevação da PA. Idealmente, deve ser prescrito um DIU, um bloqueador do SRAA e um BCC di-idropiridínico, em doses plenas toleradas e a intervalos adequados. Em situações particulares como DAC, ICC e taquiarritmias, um BB pode substituir o BCC no esquema terapêutico inicial com 3 medicações.

O uso correto de diuréticos para assegurar controle da expansão volêmica é essencial, sendo que mais da metade dos pacientes pode alcançar a meta pressórica com otimização do DIU.13 A clortalidona apresenta superioridade comparada à hidroclorotiazida.23 Em pacientes com DRC estágios 4 ou 5, DIU de alça devem ser utilizados e administrados pelo menos 2 vezes ao dia. A espironolactona, antagonista da aldosterona, é a medicação de escolha como quarto medicamento nos pacientes com HAR verdadeira, possibilitando redução da PA em média de 15-20 mmHg na PAS e de 7-10 mmHg na PAD em doses de 25 a 50 mg/dia.24 Entretanto, até 20-30% dos pacientes podem não tolerar seu uso, devido à piora da função renal, hiperpotassemia, ginecomastia ou mastalgia. Nesse caso, a amilorida pode ser utilizada (5-10 mg/dia), mas com resposta pressórica aparentemente inferior.25 O uso da clonidina como quarto fármaco está sendo avaliado no estudo brasileiro ReHOT, considerando a medida da atividade simpática e do SRAA como possíveis preditores da melhor resposta terapêutica à clonidina e à espironolactona, respectivamente.4

Nos pacientes ainda sem controle pressórico à MAPA, após a adição de espironolactona, os BB (principalmente os com efeito vasodilatador) são as medicações de quinta linha, se não contraindicados. Os alfa-agonistas centrais (clonidina e alfametildopa), os vasodilatadores diretos (hidralazina e minoxidil), ou os agonistas centrais dos receptores imidazolínicos são geralmente utilizados como medicações de sexta ou sétima linha. Também associações de múltiplos DIU (tiazídicos, de alça e espironolactona), em especial em estados edematosos, ou de BCC di-idropiridínicos e não di-idropiridínicos podem ser usados nos pacientes mais graves.

A cronoterapia orientada pela MAPA, com pelo menos uma das medicações anti-hipertensivas administrada à noite, foi capaz de melhorar o controle pressórico e reverter o padrão não-dipper desfavorável nesses pacientes, bem como reduzir a morbimortalidade CV (Quadro 3).18

Tratamento da hipertensão arterial resistente
Intervenção Grau de recomendação Nível de evidência
Institua MEV I B
Otimize tratamento com 3 medicações: clortalidona*, IECA ou BRA, e BCC† I B
Adicione espironolactona como 4ª medicação IIa B
Adicione BB como 5ª medicação† IIb C
Adicione sequencialmente simpatolíticos de ação central ou vasodilatadores diretos IIb C
Prescreva uma ou mais das medicações à noite IIb B
Confira e melhore adesão ao tratamento I C
Novas estratégias terapêuticas

Novas estratégias estão em desenvolvimento, mas são ainda consideradas experimentais. Embora seguras, não são superiores ao tratamento convencional e só devem ser utilizadas em pacientes verdadeiramente resistentes (Quadro 4).

Novas estratégias terapêuticas na hipertensão arterial resistente
Intervenção Grau de recomendação Nível de evidência
Estimulação de barorreceptores do seio carotídeo (Rheos device)26 IIb B
Denervação simpática renal27,28 IIb B
Uso de CPAP29 IIb B
Anastomose arteriovenosa central (coupler device)30 IIb B
Estimulação direta e crônica de barorreceptores do seio carotídeo

O sistema Rheos é um dispositivo programável, tipo marca-passo, implantado cirurgicamente, constituído por um gerador de impulsos que ativam os barorreceptores carotídeos por radiofrequência. O ensaio clínico Rheos Pivotal Trial não detectou benefícios significativos a longo prazo.26

Denervação simpática renal

A denervação simpática percutânea transluminal renal por cateter foi avaliada principalmente nos estudos SYMPLICITY conduzidos em pacientes com HAR. Meta-análises27,28 recentes não confirmaram os resultados promissores iniciais.

 Uso de CPAP

O conjunto das evidências sobre o efeito anti-hipertensivo de CPAP é contraditório. Contudo, como tratamento auxiliar em pacientes com SAHOS, especialmente naqueles que toleram a sua utilização por períodos superiores a 4h/noite, há evidências de que possa colaborar para restabelecer o padrão dipper.29

Anastomose arteriovenosa ilíaca central

O estudo ROX Control HTN30 demonstrou resultados promissores com reduções significativas da PA e das complicações hipertensivas nos pacientes com anastomose ilíaca central com dispositivo coupler.

 Prognóstico

Estudo de coorte retrospectivo realizado a partir de registro norte-americano indica que, após o início do tratamento anti-hipertensivo, a incidência de HAR aparente (PA não controlada com uso de 3 medicamentos) será de 0,7/100/pacientes ano, sendo que o risco relativo desses pacientes para eventos CV será de 1,47 (intervalo de confiança 95%: 1,33-1,62).31 Estudo prospectivo de 556 hipertensos resistentes (seguimento de 4,8 anos) indicou que a MAPA não controlada e a ausência de descenso noturno são importantes marcadores de risco CV.32 A condição de HAR aparente é considerada de risco independente para a ocorrência de eventos CV. (GR: IIa; NE: C). É recomendada realização da MAPA para estabelecimento do prognóstico de hipertensos com HAR verdadeira. (GR: IIa; NE: C).