Treatment-resistant hypertension
Abstract
Treatment-resistant hypertension is one of the most significant causes of poor blood pressure regulation. Patients with resistant hypertension are at a higher risk of developing comorbidities compared to the general hypertensive population. As a result, these patients have an increased incidence of disability and premature death, as well as increased treatment costs. Due to the above-mentioned, in the last decade, there has been an increase in researchers' interest in elucidating the pathogenesis, diagnosis, and treatment of resistant hypertension. However, recent data indicate that 20% of female and 24% of male patients with arterial hypertension still have uncontrolled blood pressure, despite maximum doses of three antihypertensive drugs (including a diuretic) and appropriate lifestyle measures. New treatment modalities (i.e. device-based interventions - catheter-based renal denervation and baroreceptor stimulation) offer hope for achieving adequate blood pressure regulation in these patients. In this paper, we have summarized previous knowledge about the mechanisms underlying the pathogenesis of resistant hypertension, as well as optimal diagnostic methods to differentiate true from pseudo-resistant hypertension. We have also given an overview of the current therapeutic approach, including optimal medical therapy and new treatment modalities (i.e. device-based interventions) and their role in the treatment of resistant hypertension.
References
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398(10304):957-980.
Rimoldi SF, Messerli FH, Bangalore S, Scherrer U. Resistant hypertension: what the cardiologist needs to know. Eur Heart J. 2015;36(40):2686-95.
Noubiap JJ, Nansseu JR, Nyaga UF, Sime PS, Francis I, Bigna JJ. Global prevalence of resistant hypertension: a meta-analysis of data from 3.2 million patients. Heart. 2019;105(2):98-105.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018;39(33):3021–3104.
Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, 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;51:1403–19.
Achelrod D, Wenzel U, Frey S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens. 2015;28:355–61.
Whelton PK, Robert MC, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115.
Smith SM. Epidemiology, Prognosis, and Treatment of Resistant Hypertension. Pharmacotherapy. 2013;33(10):1071-86.
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.
Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens. 2013;31(4):766-74.
Acelajado MC, Hughes ZH, Oparil S, Calhoun DA. Treatment of Resistant and Refractory Hypertension. Circ Res. 2019;124(7):1061-1070.
Hayek SS, Abdou MH, Demoss BD, Legaspi JMO, Veledar E, Deka A, et al. Prevalence of resistant hypertension and eligibility for catheter-based renal denervation in hypertensive outpatients. Am J Hypertens. 2013;26(12):1452–8.
Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens. 2001;19(11):2063-70.
Salles GF, Cardoso CR, Muxfeldt ES. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med. 2008;168(21):2340-6.
Calhoun DA. Hyperaldosteronism as a Common Cause of Resistant Hypertension. Annu Rev Med. 2013;64:233-47.
Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, et al. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension. J Hypertens. 2012;30(6):1047-55.
Hwang AY, Dietrich E, Pepine CJ, Smith SM. Resistant Hypertension: Mechanisms and Treatment. Curr Hypertens Rep. 2017 Jul;19(7):56.
Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116(6):976-90.
Grassi G, Bombelli M, Buzzi S, Volpe M, Brambilla G. Neuroadrenergic disarray in pseudo-resistant and resistant hypertension. Hypertens Res. 2014;37(6):479-83.
Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19):1245-54.
Boutouyrie P, Fliser D, Goldsmith D, Covic A, Wiecek A, Ortiz A, et al. Assessment of arterial stiffness for clinical and epidemiological studies: methodological considerations for validation and entry into the European Renal and Cardiovascular Medicine registry. Nephrol Dial Transplant. 2014;29(2):232-9.
Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, et al. Optimum and stepped care standardized antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. 2015;385(9981):1957-65.
Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med. 2012;125(1):14-22.
Salerno SM, Jackson JL, Berbano WP. Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis. Arch Intern Med. 2005;165(15):1686-94.
Sarafidis PA, Bakris GL. Resistant Hypertension: An Overview of Evaluation and Treatment. J Am Coll Cardiol. 2008;52(22):1749-57.
Pena-Hernandez C, Nugent K, Tuncel M. Twenty-Four-Hour Ambulatory Blood Pressure Monitoring. J Prim Care Community Health. 2020;11:1-8.
Lazaridis AA, Sarafidis PA, Ruilope LM. Ambulatory Blood Pressure Monitoring in the Diagnosis, Prognosis, and Management of Resistant Hypertension: Still a Matter of our Resistance? Curr Hypertens Rep. 2015;17(10):78.
Fletcher EC. Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea. Sleep. 2003:26(1):15-9.
Baumgartner I, Lerman LO. Renovascular hypertension: screening and modern management. Eur Heart J. 2011;32(13):1590-8.
Messerli FH, Bangalore S, Makani H, Rimoldi SF, Allemann Y, White CJ, et al. Flash pulmonary oedema and bilateral renal artery stenosis: the Pickering syndrome. Eur Heart J. 2011;32(18):2231-5.
Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48(11):2293-300.
Fagard RH. Resistant hypertension. Heart. 2012;98(3):254-61.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, 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(5):507-20.
Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J. 2011;32(20):2499-506.
Mourad JJ, Amodeo C, de Champvallins M, Brzozowska-Villatte R, Asmar R. Blood pressure-lowering efficacy and safety of perindopril/indapamide/amlodipine single-pill combination in patients with uncontrolled essential hypertension: a multicenter, randomized, double-blind, controlled trial. J Hypertens. 2017;35(7):1481-1495.
Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407.
Kramer HJ, Townsend RR, Griffin K, Flynn JT, Weiner DE, Rocco MV, et al. KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline. Am J Kidney Dis. 2019 Apr;73(4):437-458.
Vaclavik J, Sedlak R, Plachy M, Navratil K, Plasek J, Jarkovsky J, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069-75.
Chapman N, Chen CY, Fujita T, Hobbs FD, Kim SJ, Staessen JA, et al. Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension? J Hypertens. 2010;28(9):1796-803.
Yugar-Toledo JC, Modolo R, Faria AP, Moreno H. Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists. Vasc Health Risk Manag. 2017;13:403-411.
Dudenbostel T, Calhoun DA. Use of Aldosterone Antagonists for Treatment of Uncontrolled Resistant Hypertension. Am J Hypertens. 2017;30(2):103-109.
Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, 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(10008):2059-2068.
Rosa J, Zelinka T, Petrák O, Štrauch B, Holaj R, Widimský Jr J. Should All Patients with Resistant Hypertension Receive Spironolactone? Curr Hypertens Rep. 2016;18(11):81.
Krum H, Schlaich M, Sobotka P, Scheffers I, Kroon AA, de Leeuw PW. Novel procedure- and device-based strategies in the management of systemic hypertension. Eur Heart J. 2011 32(5):537-44.
Ewen S, Ukena C, Linz D, Kindermann I, Cremers B, Laufs U, et al. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. Hypertension. 2015;65(1):193-9.
von Arx R, Rexhaj E, Allemann Y, Moschovitis A, Windecker S, Meier B, et al. Lack of blood pressure-lowering effect of renal denervation in a drug-naive patient with pronounced arterial stiffening. Am J Med. 2014;127(9):e3-4.
Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Lobo MD. Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control Following Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial. Circulation. 2019;139:2542–2553.
Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet. 2017;390(10108):2160-2170.
Kougias P, Weakley SM, Yao Q, Lin PH, Chen C. Arterial baroreceptors in the management of systemic hypertension. Med Sci Monit. 2010;16(1):RA1–RA8.
Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010;55:619–626.
