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(Circulation. 2007;116:268-275.)
© 2007 American Heart Association, Inc.

Hypertension

The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio

Susan J. Hood, RGN; Kevin P. Taylor, MSc; Michael J. Ashby, BSc; Morris J. Brown, FMedSci

From the Clinical Pharmacology Unit, Department of Medicine, University of Cambridge (S.J.H., M.J.A., M.J.B.), and Clinical Biochemistry, Addenbrookes Hospital (K.P.T.), Cambridge, UK.

Correspondence to Professor Morris Brown, Clinical Pharmacology Unit, Box 110, Addenbrookes Hospital, Cambridge CB2 2QQ, UK. E-mail m.j.brown{at}cai.cam.ac.uk

Received December 10, 2006; accepted May 11, 2007.

Background— There is continuing variation in diagnosis and estimated prevalence of primary hyperaldosteronism. The higher estimates encourage search for adrenal adenomas in patients with elevated ratios of plasma aldosterone to renin. However, it is more likely that patients with normal plasma K⁺ and aldosterone belong to the polygenic spectrum of low-renin hypertension rather than have the same monogenic syndrome as classic Conn’s. Our primary hypothesis was that in low-renin patients with normal plasma K⁺ and aldosterone, a thiazide diuretic, bendroflumethiazide, would be as effective as spironolactone in overcoming the Na⁺ retention and lowering blood pressure. Secondary objectives were to compare the dose response for each diuretic and to evaluate amiloride as an alternative to spironolactone.

Methods and Results— Fifty-seven patients entered and 51 patients completed a placebo-controlled, double-blind, randomized crossover trial. Entry criteria included low plasma renin, normal K⁺, elevated aldosterone-renin ratio, and a previous systolic blood pressure response to spironolactone of 20 mm Hg. Two doses each of spironolactone and bendroflumethiazide were compared. The crossover also included amiloride and losartan. Outcome measures were blood pressure, plasma renin, and other biochemical markers of diuretic action. Spironolactone 100 mg and bendroflumethiazide 5 mg caused similar falls in systolic blood pressure, whereas bendroflumethiazide 2.5 mg was 5/2 mm Hg less effective in reducing blood pressure than either bendroflumethiazide 5 mg or spironolactone 50 mg (P<0.005). Amiloride 40 mg was as effective as the other diuretics. Biochemical indices of natriuresis showed bendroflumethiazide to be less effective than either spironolactone or amiloride; plasma renin rose 4-fold on spironolactone but only 2-fold on bendroflumethiazide (P=0.003).

Conclusions— In hypertensive patients with a low plasma renin but normal K⁺, bendroflumethiazide 5 mg was as effective as spironolactone 100 mg in lowering blood pressure, despite patients being selected for a previous large fall in blood pressure on spironolactone. Because this result differs from that expected in primary hyperaldosteronism, our finding argues against low-renin hypertension including a large, undiagnosed pool of primary hyperaldosteronism. However, spironolactone was the more effective natriuretic agent, suggesting that inappropriate aldosterone release or response may still contribute to the Na⁺ retention of low-renin hypertension.

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