Treatment of resistant hypertension
- David A Calhoun, MD
David A Calhoun, MD
- Professor of Medicine
- University of Alabama at Birmingham
- Raymond R Townsend, MD
Raymond R Townsend, MD
- Professor of Medicine
- Perelman School of Medicine
- University of Pennsylvania
- Section Editors
- George L Bakris, MD
George L Bakris, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Professor of Medicine
- The University of Chicago
- Norman M Kaplan, MD
Norman M Kaplan, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Clinical Professor of Internal Medicine
- University of Texas Southwestern Medical Center
Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic . Patients whose blood pressure is controlled with four or more medications are considered to have resistant hypertension.
Patients with resistant hypertension are at high risk for adverse cardiovascular events and are more likely than those with controlled hypertension to have a secondary cause, which is usually at least in part reversible.
The treatment and prognosis of resistant hypertension that is not due to secondary causes will be reviewed here. The definition, prevalence, risk factors, and evaluation of resistant hypertension and secondary causes of hypertension, such as renovascular disease and primary aldosteronism, are discussed elsewhere. (See "Definition, risk factors, and evaluation of resistant hypertension" and "Evaluation of secondary hypertension".)
DEFINITION AND GOAL BLOOD PRESSURE
Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic (selected based upon kidney function) [1,2]. Patients whose blood pressure is controlled with four or more medications are considered to have resistant hypertension.
The goal blood pressure is less than 140/90 mmHg in average-risk hypertensive patients. There is evidence supporting a lower goal blood pressure (ie, <130/80 mmHg) in patients with atherosclerotic cardiovascular disease and in patients with proteinuric chronic kidney disease. The supportive data are presented separately. (See "What is goal blood pressure in the treatment of hypertension?" and "Goal blood pressure in patients with cardiovascular disease or at high risk", section on 'Goal blood pressure' and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Blood pressure goal'.)
- Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51:1403.
- Braam B, Taler SJ, Rahman M, et al. Recognition and Management of Resistant Hypertension. Clin J Am Soc Nephrol 2017; 12:524.
- Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. JAMA 2014; 311:2216.
- Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med 2012; 125:14.
- Kassel LE, Odum LE. Our own worst enemy: pharmacologic mechanisms of hypertension. Adv Chronic Kidney Dis 2015; 22:245.
- Cappuccio FP, Kerry SM, Forbes L, Donald A. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004; 329:145.
- Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med 1991; 151:1786.
- James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507.
- Pierdomenico SD, Lapenna D, Bucci A, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005; 18:1422.
- Boudville N, Ward S, Benaroia M, House AA. Increased sodium intake correlates with greater use of antihypertensive agents by subjects with chronic kidney disease. Am J Hypertens 2005; 18:1300.
- Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008; 168:1159.
- Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension 2002; 39:982.
- Sica DA. Chlorthalidone: has it always been the best thiazide-type diuretic? Hypertension 2006; 47:321.
- Agarwal R, Sinha AD, Pappas MK, Ammous F. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study. Am J Nephrol 2014; 39:171.
- Khosla N, Chua DY, Elliott WJ, Bakris GL. Are chlorthalidone and hydrochlorothiazide equivalent blood-pressure-lowering medications? J Clin Hypertens (Greenwich) 2005; 7:354.
- Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49:839.
- Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A, Martell-Claros N. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system. J Hypertens 2010; 28:2329.
- Calhoun DA, White WB. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens 2008; 2:462.
- Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011; 57:1069.
- Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003; 16:925.
- Eide IK, Torjesen PA, Drolsum A, et al. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004; 22:2217.
- Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol 2009; 30:418.
- Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386:2059.
- Oxlund CS, Henriksen JE, Tarnow L, et al. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens 2013; 31:2094.
- Bobrie G, Frank M, Azizi M, et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. J Hypertens 2012; 30:1656.
- Hanselin MR, Saseen JJ, Allen RR, et al. Description of antihypertensive use in patients with resistant hypertension prescribed four or more agents. Hypertension 2011; 58:1008.
- Townsend RR, DiPette DJ, Goodman R, et al. Combined alpha/beta-blockade versus beta 1-selective blockade in essential hypertension in black and white patients. Clin Pharmacol Ther 1990; 48:665.
- Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015; 385:1957.
- Symplicity HTN-2 Investigators, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376:1903.
- Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373:1275.
- Schlaich MP, Sobotka PA, Krum H, et al. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med 2009; 361:932.
- Williams B. Resistant hypertension: an unmet treatment need. Lancet 2009; 374:1396.
- Davis MI, Filion KB, Zhang D, et al. Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J Am Coll Cardiol 2013; 62:231.
- Mahfoud F, Ukena C, Schmieder RE, et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013; 128:132.
- Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013; 34:2132.
- Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57:911.
- Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012; 23:1250.
- Kiuchi MG, Maia GL, de Queiroz Carreira MA, et al. Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension. Eur Heart J 2013; 34:2114.
- Oliveras A, Armario P, Clarà A, et al. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study - a randomized controlled trial. J Hypertens 2016; 34:1863.
- Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370:1393.
- Messerli FH, Bangalore S. Renal denervation for resistant hypertension? N Engl J Med 2014; 370:1454.
- de Jager RL, de Beus E, Beeftink MM, et al. Impact of Medication Adherence on the Effect of Renal Denervation: The SYMPATHY Trial. Hypertension 2017; 69:678.
- Desch S, Okon T, Heinemann D, et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 2015; 65:1202.
- Mathiassen ON, Vase H, Bech JN, et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens 2016; 34:1639.
- Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010; 56:1254.
- Illig KA, Levy M, Sanchez L, et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg 2006; 44:1213.
- Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 2010; 55:619.
- Alnima T, Scheffers I, De Leeuw PW, et al. Sustained acute voltage-dependent blood pressure decrease with prolonged carotid baroreflex activation in therapy-resistant hypertension. J Hypertens 2012; 30:1665.
- Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011; 58:765.
- Bakris GL, Nadim MK, Haller H, et al. 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; 6:152.
- Burchell AE, Lobo MD, Sulke N, et al. Arteriovenous anastomosis: is this the way to control hypertension? Hypertension 2014; 64:6.
- Faul J, Schoors D, Brouwers S, et al. Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension. J Vasc Surg 2014; 59:1078.
- Lobo MD, Sobotka PA, Stanton A, et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet 2015; 385:1634.
- Cuspidi C, Macca G, Sampieri L, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens 2001; 19:2063.
- Isaksson H, Ostergren J. Prognosis in therapy-resistant hypertension. J Intern Med 1994; 236:643.
- Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012; 125:1635.
- Salles GF, Cardoso CR, Muxfeldt ES. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med 2008; 168:2340.
- DEFINITION AND GOAL BLOOD PRESSURE
- GENERAL PRINCIPLES
- Identify and treat secondary hypertension
- Stop medications that raise the blood pressure
- Refer to a hypertension specialist
- Out-of-office blood pressure monitoring
- NONPHARMACOLOGIC THERAPY
- PHARMACOLOGIC THERAPY
- Mineralocorticoid receptor antagonists
- CHOICE OF REGIMEN
- EXPERIMENTAL THERAPIES
- Catheter-based radiofrequency ablation of renal sympathetic nerves
- Electrical stimulation of carotid sinus baroreceptors
- Central arteriovenous anastomosis
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS