In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. These three substudies were conducted to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. The researchers concluded that spironolactone is an effective treatment of resistant hypertension because this is commonly a salt-retaining condition probably due to inappropriate aldosterone secretion and amiloride seems to be an effective, well tolerated alternative to spironolactone. They suggest these findings should encourage debate about whether thresholds for diagnosis of primary aldosteronism should be reconsidered in patients presenting with resistant hypertension, and about the possibility of earlier diagnosis of primary aldosteronism to prevent development of resistant hypertension.
A commentary notes that although its superiority as fourth-line treatment for resistant hypertension is now firmly established, use of spironolactone is often limited by tolerability. It suggests eplerenone, a more selective mineralocorticoid receptor antagonist, is one alternative, but is well known to be less potent than spironolactone and its cost is often prohibitive. Therefore, the finding that amiloride was as effective as spironolactone as a fourth drug for treating resistant hypertension (6 weeks of amiloride 10 mg daily reduced clinic systolic blood pressure by 20.4 mm Hg vs reduction of 18.3 mm Hg with spironolactone 25 mg daily) is clinically important. It acknowledges that although the findings are based on an open-label extension in a subgroup of patients, they do provide a compelling reason to consider amiloride as a viable substitute for spironolactone when spironolactone is not tolerated.