The significantly greater reduction in the primary endpoint in spironolactone- versus placebo-treated patients was comparable in those with and without RHT. The evidence on which this recommendation is made is derived from three SRs and two independent RCTs that were not included in the SRs.[150-152,154,155] A third open-label study documented the blood pressure lowering effect of amiloride in a subset of 146 RHT patients who had already been treated with spironolactone, placebo, bisoprolol, or doxazosin in the Pathway-2 RCT.[153] The results of this substudy were not included in the three SRs since it was published later. The Work Group did not consider this substudy in its development of the recommendation or determination of the confidence in the quality of the evidence. Among the five RCTs included in the SR by Liu et al. (2017) spironolactone consistently lowered office and ambulatory or home SBP and DBP in the pooled analysis.[150] In this analysis, spironolactone also lowered SBP by 4.5 mm Hg compared to atenolol, candesartan, or alpha methyldopa, a statistically significant effect. The strength of evidence to support the efficacy of spironolactone to lower both SBP and DBP compared to either placebo or other drugs previously listed was considered to be high with a low risk of bias. Similar conclusions were reached after review of the SR by Wang et al. (2016).[151] In contrast, the strength of the evidence represented by the 19 studies of 2,758 patients with RHT in the SR by Makai et al. (2017) was very low.[152] Studies of both spironolactone and eplerenone (MRAs) were combined for this analysis so it was impossible to determine if the efficacy of each was equivalent to the other. 