Current Hypertension Reports

, 13:347

Resistant Hypertension: Concepts and Approach to Management



Resistant hypertension (RH), defined simply, is blood pressure (BP) requiring the use of four or more antihypertensive agents, whether controlled or uncontrolled. RH is an increasingly common problem in elderly patients and may affect as many as 20% of the hypertensive population. Unfortunately, at least 30% of patients evaluated for RH are actually adequately controlled when more carefully assessed by home BP monitoring or ambulatory BP monitoring, thus representing a white coat effect. It is also essential to exclude pseudoresistance resulting from improper BP recording techniques or failure of the patient to adhere to the prescribed treatment regimen. Concurrent use of drugs that may interfere with prescribed antihypertensive agents, including many over the counter herbal preparations, must also be excluded. The underlying mechanisms principally driving true RH include pathophysiologic abnormalities of aldosterone signaling, sodium and water retention, excessive sympathetic nervous system activity, and obstructive sleep apnea. Appropriate treatment regimens will usually include an inhibitor of the renin-angiotensin-aldosterone system, a calcium channel blocker, and a diuretic. An aldosterone receptor blocker can be instituted at any step, and is very effective as a fourth drug. Beta-blockers can also be integrated into these treatment plans and may be especially helpful when excessive sympathetic nervous system activity is suspected. Novel device therapies that interrupt sympathetic nerve stimulation at the carotid sinus and kidney are under investigation, and may add entirely new directions in the management of RH. What is most important is that treatment regimens should be targeted to specific patient profiles.


Resistant hypertension Uncontrolled hypertension Blood pressure Mechanisms Management: Treatment Monitoring White coat effect Pseudoresistance Antihypertensive agents Obstructive sleep apnea Sympathetic nervous system activity Spironolactone 


  1. 1.
    Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high BP: the JNC 7 report. JAMA. 2003;289:2560–72.PubMedCrossRefGoogle Scholar
  2. 2.
    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 BP Research. Hypertension. 2008;51:1403–19.PubMedCrossRefGoogle Scholar
  3. 3.
    Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA. 2003;290:199–206.PubMedCrossRefGoogle Scholar
  4. 4.
    Peralta CA, Hicks LS, Chertow GM, et al. Control of hypertension in adults with chronic kidney disease in the United States. Hypertension. 2005;45:1119–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of BP control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens. 2002;4:393–404.CrossRefGoogle Scholar
  6. 6.
    Egan BM, Zhao Y,Shakaib, Rehman, SU, et al. Treatment resistant hypertension in a community-based practice network. J Clin Hypertens. 2009; OR-12.Google Scholar
  7. 7.
    Ma J, Lee KV, Stafford RS. Changes in antihypertensive prescribing during US outpatient visits for uncomplicated hypertension between 1993 and 2004. Hypertension. 2006;48:846–52.PubMedCrossRefGoogle Scholar
  8. 8.
    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;168:1159–64.PubMedCrossRefGoogle Scholar
  9. 9.
    Levey AS, Eckardt K-U, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67:2089–100.PubMedCrossRefGoogle Scholar
  10. 10.
    Khosla N, Kalaitzidis R, Bakris GL. The kidney, hypertension, and remaining challenges. Med Clin North Am. 2009;93:697–715.PubMedCrossRefGoogle Scholar
  11. 11.
    White CJ, Jaff MR, Haskal ZJ, et al. Indications for renal arteriography at the time of coronary arteriography: a science advisory from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Councils on Cardiovascular Radiology and Intervention and on Kidney in Cardiovascular Disease. Circulation. 2006;114:1892–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Burnier M, Schneider MP, Chioléro A, et al. Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. J Hypertens. 2001;19:335–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Moser M, Setaro JF. Resistant or difficult-to-control hypertension. N Engl J Med. 2006;355:385–92.PubMedCrossRefGoogle Scholar
  14. 14.
    de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory BP monitoring. Hypertension. 2011;57:898–902.PubMedCrossRefGoogle Scholar
  15. 15.
    Garcia-Donaire JA, Segura J, Cerezo C, et al. True resistant hypertension: optimal cut-off ambulatory BP level for diagnosis and effect of spironolactone. J Clin Hypertens. 2011;13 Suppl 1:OR-20.Google Scholar
  16. 16.
    Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol. 2008;52:1749–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Sander GE. Drugs that increase BP. Therapy. 2011;8:275–82.CrossRefGoogle Scholar
  18. 18.
    Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens. 2008;10:556–66.CrossRefGoogle Scholar
  19. 19.
    Cohen PA, Ernst E. Safety of herbal supplements: a guide for cardiologists. Cardiovasc Ther. 2010;28:246–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs. 2001;61:2163–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Pimenta E, Gaddam KK, Pratt-Ubunama MN, et al. Relation of dietary salt and aldosterone to urinary protein excretion in subjects with resistant hypertension. Hypertension. 2008;51:339–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Mosso L, Carvajal C, González A, et al. Primary aldosteronism and hypertensive disease. Hypertension. 2003;42:161–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Joint National Committee. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP. Arch Intern Med. 1997;157:2413–46.CrossRefGoogle Scholar
  24. 24.
    Calhoun DA, Nishizaka MK, Zaman MA, et al. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40:892–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Gallay BJ, Ahmad S, Xu L, Toivola B, et al. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37:699–705.PubMedCrossRefGoogle Scholar
  26. 26.
    Eide IK, Torjesen PA, Drolsum A, et al. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens. 2004;22:2217–26.PubMedCrossRefGoogle Scholar
  27. 27.
    Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky Jr J. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens. 2003;17:349–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol. 2009;30:418–24.PubMedCrossRefGoogle Scholar
  29. 29.
    Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;19:2271–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Sim JJ, Yan EH, Liu IL, Rasgon SA, et al. Positive relationship of sleep apnea to hyperaldosteronism in an ethnically diverse population. J Hypertens. 2011;29:1553–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Gonzaga CC, Gaddam KK, Ahmed MI, et al. Severity of obstructive sleep apnea is related to aldosterone status in subjects with resistant hypertension. J Clin Sleep Med. 2010;6:363–8.PubMedGoogle Scholar
  32. 32.
    Pimenta E, Gaddam KK, Oparil S. Effects of dietary sodium reduction on BP in subjects with resistant hypertension: results from a randomized trial. Hypertension. 2009;54:475–81.PubMedCrossRefGoogle Scholar
  33. 33.
    Yugar-Toledo JC, Martin JF, Krieger JE, et al. Gene variation in resistant hypertension: multilocus analysis of the angiotensin 1-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase genes. DNA Cell Biol. 2011;30:555–64.PubMedCrossRefGoogle Scholar
  34. 34.
    George J, Struthers AD. Evaluation of the aldosterone-blocking agent eplerenone in hypertension and heart failure. Expert Opin Pharmacother. 2007;8:3053–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003;16(11 Pt 1):925–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on BP in subjects with resistant hypertension. Hypertension. 2007;49:839–45.PubMedCrossRefGoogle Scholar
  37. 37.
    de Souza F, Muxfeldt E, Fiszman R, et al. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension. 2010;55:147–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A, et al. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system. J Hypertens. 2010;28:2329–35.PubMedCrossRefGoogle Scholar
  39. 39.
    Kobayashi S, Clemmons DR, Nogami H, et al. Tubular hypertrophy due to work load induced by furosemide is associated with increases of IGF-1 and IGFBP-1. Kidney Int. 1995;47:818–28.PubMedCrossRefGoogle Scholar
  40. 40.
    Broekhuysen J, Deger F, Douchamps J, Ducarne H, et al. Torasemide, a new potent diuretic. Double-blind comparison with furosemide. Eur J Clin Pharmacol. 1986;31(Supp):29–34.PubMedCrossRefGoogle Scholar
  41. 41.
    Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office BP. Hypertension. 2006;47:352–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Khosla N, Chua DY, Elliott WJ, et al. Are chlorthalidone and hydrochlorothiazide equivalent blood-pressure-lowering medications? J Clin Hypertens. 2005;7:354–6.CrossRefGoogle Scholar
  43. 43.
    Menon DV, Arbique D, Wang Z, et al. Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients. J Clin Endocrinol Metab. 2009;94:1361–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Raheja P, Arbique D, Wang Z, et al. Spironolactone reverses chlorthalidone-induced sympathetic activation in hypertensive patients. J Clin Hypertens. 2011;13 Suppl 1:OR-6.Google Scholar
  45. 45.
    Mann SJ. Drug therapy for resistant hypertension: simplifying the approach. J Clin Hypertens. 2011;13:120–30.CrossRefGoogle Scholar
  46. 46.
    Jamerson K, Weber MA, Bakris GL, for the ACCOMPLISH Trial Investigators, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–28.PubMedCrossRefGoogle Scholar
  47. 47.
    Jamerson KA, Devereux R, Bakris GL, et al. Efficacy and duration of benazepril plus amlodipine or hydrochlorothiazide on 24-hour ambulatory systolic BP control. Hypertension. 2011;57:174–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Giles TD, Houston MC. Do diuretics diminish the predicted benefits on ischemic heart disease events of lowering BP in hypertension? Messages from ALLHAT, ACCOMPLISH, and ACCORD. J Clin Hypertens. 2010;12:469–71.Google Scholar
  49. 49.
    Hummel D, Raff U, Schwarz TK, et al. Dihydropyridine calcium antagonists are associated with increased albuminuria in treatment-resistant hypertensives. J Nephrol. 2010;23(5):563–8.PubMedGoogle Scholar
  50. 50.
    Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis. 2007;49:12–26.PubMedCrossRefGoogle Scholar
  51. 51.
    Verdecchia P, Sleight P, Mancia G, et al. Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the ongoing telmisartan alone and in combination with ramipril global end point trial and the telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease. Circulation. 2009;120(14):1380–9.PubMedCrossRefGoogle Scholar
  52. 52.
    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;51:69–76.PubMedCrossRefGoogle Scholar
  53. 53.
    Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011;34:1270–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Ziegler MG, Milic M, Sun P. Antihypertensive therapy for patients with obstructive sleep apnea. Curr Opin Nephrol Hypertens. 2011;20:50–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Weber MA, Black H, Bakris G, et al. A selective endothelin-receptor antagonist to reduce BP in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1423–31.PubMedCrossRefGoogle Scholar
  56. 56.
    Ng MM, Sica DA, Frishman WH. Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension. Cardiol Rev. 2011;19:52–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Lohmeier TE, Iliescu R. Chronic lowering of BP by carotid baroreflex activation: mechanisms and potential for hypertension therapy. Hypertension. 2011;57:880–6.PubMedCrossRefGoogle Scholar
  58. 58.
    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;56:1254–8.PubMedCrossRefGoogle Scholar
  59. 59.
    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;373:1275–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Heart and Vascular InstituteTulane University School of MedicineNew OrleansUSA

Personalised recommendations