[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. Furthermore, the collective risk of bias among the studies was considered to be a serious limitation even though 24-hour SBP and DBP were significantly reduced when assessed by ABPM but not by office DBP. When Krieger et al. (2018) compared the effects of clonidine on office and 24-hour blood pressure with those of low-dose spironolactone in patients with RHT with multiple comorbidities excluded, there were no significant differences but there was considerable variability in the responses of the patients.[154] Collectively, there was sufficient concern about either imprecision or risk of bias among the SRs and RCT supporting the addition for adding spironolactone as the preferred fourth agent in patients with RHT still not controlled on three drugs to make only a Weak for recommendation. Although of considerable clinical interest, the findings that spironolactone reduced cardiovascular outcomes in the TOPCAT cohort with preserved ejection fraction heart failure and RHT similarly to those without RHT was not considered in the above assessment because of the serious limitations of the study design as well as serious imprecision.[155] In addition, it is likely that this population of preselected patients with heart failure are phenotypically different from other patients with RHT. Before adding a fourth drug to the treatment regimen, medication adherence should be assessed and the benefits of non-pharmacologic therapy should be reinforced in every patient who meets the criteria for RHT. Because of the frequency with which medication non-adherence occurs in this population, the term apparent treatment resistant hypertension has appeared in the literature with increasing frequency. 