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Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg ⁄ 1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to )1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA ⁄ ASI has not yet been tested. J Clin Hypertens (Greenwich). 2013; 15:186-192. Ó2012 Wiley Periodicals, Inc.Aldosterone plays an important role in blood pressure (BP) control and maintaining potassium and sodium homeostasis and in the pathophysiology of cardiovascular and renal disease.1-4 A relative aldosterone excess predicts hypertension onset 5 and aldosterone is believed to play a critical role in mediating and aggravating resistant hypertension, 6 a common clinical problem that affects 20% to 28% of patients with hypertension. 7,8 It was previously thought that primary aldosteronism is present in <1% of unselected hypertensive patients, but more recent estimates suggest that it affects closer to 10%, and these patients tend to have higher incidences of cardiovascular (CV) damage when controlled for sex, age, and BP status. Thus, aldosterone blockade represents an attractive therapeutic approach to lower BP and to reduce the risk of CV events and end-organ damage.One approach for blocking the effects of aldosterone is to prevent its binding to mineralocorticoid receptors, and two mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, have been shown to be effective for the treatment of hypertension and heart failure.10-14 A reduction in BP with spironolactone was associated with reduction in cardiac mass and improvement in diastolic function in patients with resistant hypertension. 15 However, MRAs induce a counter-regulatory increase in aldosterone concentration, which may limit the efficacy of mineralocorticoid receptor (MR) blockade by stimulating MR-independent effects of aldosterone. 16 Indeed, aldoste...

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