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Resistant hypertension

Resistant hypertension

Resistant hypertension is defined as persistent elevation of blood pressure above 140/90 in patients who are adhering to a triple drug regimen including a diuretic, in which three drugs have been prescribed in maximum recommended and tolerated doses for at least three months.1 Roughly 21% of all patients with hypertension meet the American Heart Association definition of resistant hypertension.

The pathogenesis of resistant hypertension appears to be multifactorial,2,3 with epidemiological studies demonstrating an association with older age, obesity, impaired renal function and diabetes mellitus.4,5,6

Patients with resistant hypertension typically have elevated systemic vascular resistance and expanded plasma volume in the presence of normal cardiac output.7,8 Before diagnosing resistant hypertension, clinicians must exclude medication nonadherence and white coat syndrome which are the most common causes of false high blood pressure.9,10

All patients with resistant hypertension should be counseled about lifestyle modifications to lower blood pressure. Sodium intake is a major factor contributing to resistant hypertension. Meta-analysis of clinical trials has indicated that sodium restriction to approximately 1.7 g/day is associated with a reduction in office blood pressure by 8/3 mmHg in patients with uncomplicated hypertension. The antihypertensive effect of sodium restriction is even more pronounced in patients with resistant hypertension.11 Physical inactivity has been identified in more than 40% of patients, and a randomized trial involving patients with resistant hypertension showed that a training programme consisting of walking on a treadmill 3 times a week for 8 to 12 weeks significantly reduced ambulatory blood pressure by 6/3 mmHg compared with a sedentary control group.12

Secondary hypertension is detected in 5-10% of all patients with hypertension,13,14 however, several secondary forms of hypertension are more prevalent in resistant hypertension than in uncomplicated hypertension. For example, obstructive sleep apnea is observed in 30-40% of patients with hypertension and 60-70% of patients with resistant hypertension,15 and primary aldosteronism is present in 5-10% of all patients with hypertension and 7-20% of patients with resistant hypertension.16,17,18

Initial therapy for resistant hypertension

Pharmacological treatment for patients with resistant hypertension should begin with optimization of diuretic use. A prospective observational study in patients with resistant hypertension demonstrated that chlorthalidone, a thiazide-like diuretic, is at least twice as potent as hydrochlorothiazide a thiazide-type diuretic, in lowering blood pressure.19

After optimizing the diuretic, the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker should be prescribed for resistant hypertension. An optimum fourth-line therapy for resistant hypertension has not been extensively investigated, but in a randomized, double-blind trial (ASPIRANT), 25 mg/day spironolactone reduced 24-hour blood pressure by 10 mmHg compared with placebo in patients with resistant hypertension.20 An α-blocker is an alternative to spironolactone, particularly in patients undergoing screening for primary aldosteronism since plasma renin activity and serum aldosterone levels are not affected by α-adrenergic receptor blockade.21 β-Blockers should be used as the fifth-line drug therapy in the absence of congestive heart failure or prior myocardial infarction.

Device therapy for resistant hypertension

Devices to treat resistant hypertension mainly target the sympathetic nervous system, which is known to contribute to the pathogenesis of essential hypertension and many forms of secondary hypertension.22 These devices, however, are not uniformly successful in treating resistant hypertension. Chronic electrical stimulation of the carotid sinus nerves with a surgically implantable device, which is designed to trigger baroreflex-mediated inhibition of sympathetic nerve activity, has been shown to reduce blood pressure in 54% of patients with resistant hypertension.23 Catheter-based renal sympathetic denervation is another potential therapeutic strategy for resistant hypertension. This technique uses radiofrequency energy to ablate renal nerves alongside renal arteries in the adventitial layers.24


Treating resistant hypertension in patients who are already prescribed 3 or more drugs is challenging. Selection of additional blood pressure lowering agents should be based not only on their antihypertensive efficacy, but also on their incremental cost, the adverse effects profile and their potential cardiovascular benefits. Half of patients with uncontrolled hypertension while taking 3 or more antihypertensive drugs are prescribed medications at suboptimal doses and less than 5% are treated with mineralocorticoid receptor antagonists. Therefore, optimization of the patient’s antihypertensive regimen should be performed prior to extensive investigation for secondary hypertension.25   


  1. Chobanian AV, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC report. JAMA 2003;289(19):2560-72.
  2. Egan BM, et al. Uncontrolled and apparent treatment resistant hypertension in the United States 1988 to 2008. Circulation 2011;124(9):1046-58.
  3. Sarafidis PA, et al. Resistant hypertension - its identification and epidemiology. Nat Rev Nephrol 2013;9(1)51-8.
  4. Daugherty SL, et al. The association between medication adherence and treatment intensification with blood pressure control in resistant hypertension. Hypertension 2012;60(2):303-9.
  5. Shimbo D, et al. The contributions of unhealthy lifestyle factors to apparent resistant hypertension. J Hypertens 2013;31(2):370-6.
  6. De Nieola L, et al. Prevalence and prognostic role of resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol 2013;61(24):2461-7.
  7. Toler SJ, et al. Resistant hypertension comparing hemodynamic management to specialist care. Hypertension 2002;39(5):982-8.
  8. Gaddam KK, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone and persistent intravascular volume expansion. Arch Intern Ped. 2008;168(11):1159-64.  
  9. De la Sierra A, 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.
  10. Zeller A, et al. An adherence self-reported questionnaire facilitates the differentiation between nonadherence and nonresponse to antihypertensive treatment. J Clin Epidemiol 2008;61(3):282-8.
  11. He FJ, et al. Effect of longer term modest salt reduction on blood pressure. Br Med J 2013;346:F1 395.
  12. Dimeo F, et al. Aerobic exercise reduces blood pressure in resistant hypertension. Hypertension 2012;60(3):653-8.
  13. Mancia G, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. J Hypertens 2013;31(7):1281-1357.
  14. National Clinical Guideline Centre (UK). Hypertension: the clinical management of primary hypertension in adults: update of clinical guidelines 18 and 34. 2011. Available online.
  15. Pedrosa RP, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011;58(5):811-7.
  16. Umpierrrez GE, et al. Primary aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care 2007;30(7):1699-1703.
  17. Calhoun DA, et al. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002;40(6):892-6.
  18. Sang X, et al. Prevalence of and risk factors for primary aldosteronism among patients with resistant hypertension in China. J Hypertens 2013;31(7):1465-71.
  19. Plerzan MA, et al. Meta-analysis of dose response relationships for hydrochlorothiazide, chlorthalidone and bendroflumethiazide on blood pressure, serum potassium and urate. Hypertension 2012;59(6):1104-9.
  20. Valarik 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.
  21. Funder JW, et al. Case detection, diagnosis and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93(9):3266-81.
  22. Kontak AC, et al. Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism. J Clin Endocrinol Metab 2010;95(10):4756-61.
  23. Bisognans JD, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: Results from the double blind, randomized, placebo controlled Rheos Pivolol trial. J Am Coll Cardiol 2011;58(7):765-73.
  24. Ester MD, et al. Renal sympathetic denervation in patients with treatment resistant hypertension (the SIMPLICITY HTN-Z trial): A randomized controlled trial. Lancet 2010 376(9756):1903-9.
  25. Egan BM, 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.  

Omar Salah Awwad

Professor of Cardiology
Department of Cardiology
Ain Shams University
resistant hypertension
resistant hypertension causes
Hypertension treatment