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01-10-2014 | Resistant Hypertension (E Pimenta, Section Editor)

Resistant or Refractory Hypertension: Are They Different?

Authors: Rodrigo Modolo, Ana Paula de Faria, Aurélio Almeida, Heitor Moreno

Published in: Current Hypertension Reports | Issue 10/2014

Abstract

Resistant hypertension (RHTN) consists in a condition where blood pressure (BP) levels remain uncontrolled despite the use of at least three drugs or if the control happens with four or more drugs. Throughout the last 50 years, it has been increasingly studied, and its phenotypes have been identified. The term refractory hypertension has been used concurrently with RHTN all those years, but in the last decade, it has been applied to the most afflicted part of RHTN—defined as the uncontrolled RHTN or as the uncontrolled RHTN who needs five or more drugs. Differences between those two phenotypes are being recently identified, especially classifying refractory subjects as having more: (1) cardiovascular risk, (2) target organ damage, (3) African-descending race, (4) coronary heart disease and myocardial ischemia, (5) aldosterone excess, (6) deregulation of adipokines, and (7) possible sympathetic hyperactivation. We review the most important studies in both resistant and refractory hypertension to gather the up-to-date data regarding the characteristics of these two high-risk groups of patients.

Vandyne JR. Iproniazid in the treatment of resistant hypertension—a preliminary-report on 20 intractable cases. J Am Geriatr Soc. 1960;8(6):454–62.

Lee RE, Seligmann AW, Clark MA, Borhani NO, Queenan JT, Obrien ME. Therapeutically refractory hypertension - causative factors, and medical management with chlorothiazide and other agents. Ann Intern Med. 1958;49(5):1129–37.PubMedCrossRef

Heller R. Merriam-Webster Inc. Merriam-Webster’s first dictionary. Springfield, Mass.: Merriam-Webster; 2012.

Gifford RW, Tarazi RC. Resistant hypertension—diagnosis and management. Ann Intern Med. 1978;88(5):661–5.PubMedCrossRef

Gifford RW. Resistant hypertension—introduction and definitions. Hypertension. 1988;11(3):S65–6.

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(6):1403–19. doi:10.1161/Hypertensionaha.108.189141.PubMedCrossRef

Martell N, Rodriguez-Cerrillo M, Grobbee DE, Lopez-Eady MD, Fernandez-Pinilla C, Avila M, et al. High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Blood Press. 2003;12(3):149–54. doi:10.1080/08037050310009950.PubMedCrossRef

Ram CVS. Review of resistant hypertension. Curr Hypertens Rep. 2006;8(5):398–402. doi:10.1007/s11906-006-0085-9.PubMedCrossRef

Silverstein RL, Ram CVS. Resistant hypertension. Prim Care. 2008;35(3):501. doi:10.1016/j.pop.2008.03.002.PubMedCrossRef

10.

Sander GE, Giles TD. Resistant hypertension: concepts and approach to management. Curr Hypertens Rep. 2011;13(5):347–55. doi:10.1007/s11906-011-0226-7.PubMedCrossRef

11.••

Acelajado MC, Pisoni R, Dudenbostel T, Dell’Italia LJ, Cartmill F, Zhang B, et al. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens. 2012;14(1):7–12. doi:10.1111/j.1751-7176.2011.00556.x. This manuscript analyzed 304 patients with resistant hypertension, finding the prevalence and characteristic of the 29 that were classified as presenting refractory hypertension. Interestingly, although the groups had similar aldosterone levels, the response to spironolactone was higher in resistant ones.CrossRef

12.

Moreno H, Coca A. Resistant and refractory hypertension: reflections on pathophysiology and terminology. Blood Press. 2012;21(4):209–10. doi:10.3109/08037051.2012.701419.PubMedCrossRef

13.••

Calhoun DA, Booth 3rd JN, 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. 2013. 2014; 63(3):451–8 doi:10.1161/HYPERTENSIONAHA.113.02026. This work evaluated 14,809 subjects from the REGARDS study, dividing them in resistant (controlled and uncontrolled) and refractory hypertension - with the proposed new definition, acknowledging some predictors of refractoriness comparing to resistant hypertension.

14.

Veglio F, Rabbia F, Riva P, Martini G, Geneva GC, Milan A, et al. Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension. Clin Exp Hypertens. 2001;23(3):203–11. doi:10.1081/Ceh-100102660.PubMedCrossRef

15.

Verdecchia P. Using out of office blood pressure monitoring in the management of hypertension. Curr Hypertens Rep. 2001;3(5):400–5.PubMedCrossRef

16.

Modolo R, Ruggeri Barbaro N, de Faria AP, Rodrigues Sabbatini A, Paganelli MO, Fontana V, et al. The white-coat effect is an independent predictor of myocardial ischemia in resistant hypertension. Blood Press. 2014. doi:10.3109/08037051.2014.883194.

17.

Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens. 2005;18(11):1422–8. doi:10.1016/j.amhyper.2005.05.014.PubMedCrossRef

18.•

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–U112. doi:10.1161/Circulationaha.111.068064. This large retrospective cohort, evaluating 250,750 subjects showed an incidence of 1.9 % of resistant hypertension after 1.5 years of treatment. A more extensive follow-up revealed a higher risk of cardiovascular events in these resistant patients.PubMedCrossRefPubMedCentral

19.

Sim JJ, Bhandari SK, Shi JX, Liu ILA, Calhoun DA, McGlynn EA, et al. Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc. 2013;88(10):1099–107. doi:10.1016/j.mayocp.2013.06.017.PubMedCrossRef

20.

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. doi:10.1097/00004872-200111000-00018.PubMedCrossRef

21.

Martins LC, Figueiredo VN, Quinaglia T, Boer-Martins L, Yugar-Toledo JC, Martin JFV, et al. Characteristics of resistant hypertension: ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness. J Hum Hypertens. 2011;25(9):532–8. doi:10.1038/Jhh.2010.95.PubMedCrossRef

22.

Howard VJ, Cushman M, Pulley L, Gomez CR, Go RC, Prineas RJ, et al. The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135–43. doi:10.1159/000086678.PubMedCrossRef

23.

Ubaid-Girioli S, de Souza LA, Yugar-Toledo JC, Martins LC, Ferreira-Melo S, Coelho OR, et al. Aldosterone excess or escape: treating resistant hypertension. J Clin Hypertens. 2009;11(5):245–52. doi:10.1111/j.1751-7176.2009.00110.x.CrossRef

24.

de Faria APC, Demacq C, Figueiredo VN, Moraes CH, Santos RC, Sabbatini AR, et al. Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension. Hypertens Res. 2013;36(12):1067–72. doi:10.1038/Hr.2013.92.PubMedCrossRef

25.

Salles GF, Fiszman R, Cardoso CRL, Muxfeldt ES. Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension. Hypertension. 2007;50(4):723–8. doi:10.1161/Hypertensionaha.107.093120.PubMedCrossRef

26.

de Faria APC, Fontana V, Modolo R, Barbaro NR, Sabbatini AR, Pansani IF, et al. Plasma 8-isoprostane levels are associated with endothelial dysfunction in resistant hypertension. Clin Chim Acta. 2014;433:179–83. doi:10.1016/j.cca.2014.03.009.PubMedCrossRef

27.

Brambilla G, Bombelli M, Seravalle G, Cifkova R, Laurent S, Narkiewicz K, et al. Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study. J Hypertens. 2013;31(10):2018–24. doi:10.1097/Hjh.0b013e328363823f.PubMedCrossRef

28.

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. doi:10.1161/HYPERTENSIONAHA.113.01448.PubMedCrossRef

29.

Gijon-Conde T, Graciani A, Banegas JR. Resistant hypertension: demography and clinical characteristics in 6292 patients in a primary health care setting. Rev Esp Cardiol. 2014. doi:10.1016/j.recesp.2013.09.029.PubMed

30.•

Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlof B, Poulter NR, et al. Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011;29(10):2004–13. doi:10.1097/Hjh.0b013e32834a8a42. This analysis of the previous ASCOT study showed significant determinants of developing resistant hypertension such as systolic blood pressure, diabetes, left ventricular hypertrophy, male gender, obesity, fasting glucose, and alcohol intake. Hence the randomization for the statin use group reduced the risk of developing resistant hypertension.PubMedCrossRef

31.

Fontana V, de Faria AP, Barbaro NR, Sabbatini AR, Modolo R, Lacchini R, et al. Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension. J Am Soc Hypertens. 2013. doi:10.1016/j.jash.2013.12.001.PubMed

32.

MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335(8692):765–74.PubMedCrossRef

33.

Wong ND, Lopez VA, L’Italien G, Chen R, Kline SE, Franklin SS. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003–2004. Arch Intern Med. 2007;167(22):2431–6. doi:10.1001/archinte.167.22.2431.PubMedCrossRef

34.

Allman KG, Muir A, Howell SJ, Hemming AE, Sear JW, Foex P. Resistant hypertension and preoperative silent-myocardial-ischemia in surgical patients. Brit J Anaesth. 1994;73(5):574–8. doi:10.1093/Bja/73.5.574.PubMedCrossRef

35.

Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690–7. doi:10.1161/HYPERTENSIONAHA.108.119883.PubMedCrossRef

36.

Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989;14(2):177–83.PubMedCrossRef

37.

Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31(1):68–72.PubMedCrossRef

38.

DiBona GF. Nervous kidney—interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function. Hypertension. 2000;36(6):1083–8.PubMedCrossRef

39.

Ferrario CM, Gildenberg PL, McCubbin JW. Cardiovascular effects of angiotensin mediated by the central nervous system. Circ Res. 1972;30(3):257–62.PubMedCrossRef

40.

Grassi G, Seravalle G, Dell’Oro R, Trevano FQ, Bombelli M, Scopelliti F, et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens. 2003;21(9):1761–9. doi:10.1097/01.hjh.0000084718.53355.69.PubMedCrossRef

41.

Vasan RS, Evans JC, Larson MG, Wilson PWF, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351(1):33–41. doi:10.1056/Nejmoa033263.PubMedCrossRef

42.

Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among with resistant black and white subjects hypertension. Hypertension. 2002;40(6):892–6. doi:10.1161/01.Hyp.0000040261.30455.B6.PubMedCrossRef

43.

Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistent hypertension: a clue to efficient treatment. J Hypertens. 2004;22(11):2217–26. doi:10.1097/00004872-200411000-00026.PubMedCrossRef

44.

Umpierrez GE, Cantey P, Smiley D, Palacio A, Temponi D, Luster K, et al. Primary aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care. 2007;30(7):1699–703. doi:10.2337/Dc07-0031.PubMedCrossRef

45.

Sabbatini AR, Faria AP, Barbaro NR, Gordo WM, Modolo RG, Pinho C, et al. Deregulation of adipokines related to target organ damage on resistant hypertension. J Hum Hypertens. 2013. doi:10.1038/jhh.2013.118.

46.

Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, et al. Characterization of resistant hypertension—association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159–64. doi:10.1001/archinte.168.11.1159.PubMedCrossRefPubMedCentral

47.

Menon DV, Arbique D, Wang Z, Adams-Huet B, Auchus RJ, Vongpatanasin W. Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients. J Clin Endocrinol Metab. 2009;94(4):1361–6. doi:10.1210/Jc.2008-2660.PubMedCrossRefPubMedCentral

48.

Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. doi:10.1056/Nejmoa1402670.PubMedCrossRef

49.

Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150(11):776–83.PubMedCrossRefPubMedCentral

50.

Caprio M, Feve B, Claes A, Viengchareun S, Lombes M, Zennaro MC. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. Faseb J. 2007;21(9):2185–94. doi:10.1096/fj.06-7970com.PubMedCrossRef

51.

Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548–56. doi:10.1210/jc.2004-0395.PubMedCrossRef

52.

Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero JR, et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation. 2008;117(17):2253–61. doi:10.1161/CIRCULATIONAHA.107.748640.PubMedCrossRefPubMedCentral

53.

Moraes CD, Figueiredo VN, de Faria APC, Barbaro NR, Sabbatini AR, Quinaglia T, et al. High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension. J Hum Hypertens. 2013;27(4):225–30. doi:10.1038/Jhh.2012.29.CrossRef

Title: Resistant or Refractory Hypertension: Are They Different?
Authors: Rodrigo Modolo
Ana Paula de Faria
Aurélio Almeida
Heitor Moreno
Publication date: 01-10-2014
Publisher: Springer US
Published in: Current Hypertension Reports / Issue 10/2014
Print ISSN: 1522-6417
Electronic ISSN: 1534-3111
DOI: https://doi.org/10.1007/s11906-014-0485-1

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