Treatment of Resistant and Refractory Hypertension

Abstract

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

Keywords: chlorthalidone; goals; humans; hyperaldosteronism; spironolactone.

Figure 1.

Estimated prevalence of common causes of pseudo-treatment resistance. Reference: Bhatt H, Siddiqui M, Judd E, Oparil S and Calhoun D. Prevalence of pseudoresistant hypertension due to inaccurate blood pressure measurement. J Am Soc Hypertens. 2016;10:493-9.

Figure 2.

Mean 24-hour urinary aldosterone (UAldo) levels to quartiles of body mass index (BMI) in men (black columns) and women (white columns) with resistant hypertension. Reference: Dudenbostel T, Ghazi L., Liu M., Li P., Oparil S., Calhoun DA. Body mass index predicts 24-hr urinary aldosterone levels in patients with resistant hypertension. Hypertension. 2016.

Figure 3.

Relation between baseline plasma renin, aldosterone, and the serum aldosterone and renin concentration (ARR) ratio and the home systolic blood pressure response to spironolactone in the PATHWAY-2 study. Reference: Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, Ford I, Cruickshank JK, Caulfield MJ, Padmanabhan S, Mackenzie IS, Salsbury J, Brown MJ. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018;6(6):464-475. doi: 10.1016/S2213-8587(18)30071-8.