Diagnostic Accuracy of the Aldosterone–to–Active Renin Ratio for Detecting Primary Aldosteronism

Stefan Pilz; Martin H. Keppel; Christian Trummer; Verena Theiler-Schwetz; Marlene Pandis; Valentin Borzan; Matthias Pittrof; Barbara Obermayer-Pietsch; Martin R. Grübler; Nicolas Verheyen; Vinzenz Stepan; Andreas Meinitzer; Jakob Voelkl; Winfried März; Andreas Tomaschitz

Disclosures

J Endo Soc. 2019;3(9):1748-1758. 

In This Article

Discussion

This prospective diagnostic accuracy study in hypertensive patients showed that the area under the ROC curve for the AARR at the first study visit in detecting PA was 0.973 (95% CI, 0.956 to 0.990). The SIT also had good diagnostic accuracy, and we found good intraindividual reproducibility of the AARR.

The results from the GECOH study substantially add to the limited knowledge on the diagnostic accuracy of the AARR in detecting PA. Our findings are roughly in line with those of a meta-analysis of 974 patients from nine studies that reported a sensitivity, specificity, and area under the ROC of the AARR in detecting PA of 0.89 (95% CI, 0.84 to 0.93), 0.96 (95% CI, 0.95 to 0.98), and 0.985, respectively.[14] Methodological differences and limitations are, however, inherent in the existing literature on the diagnostic accuracy of the AARR and account for a relatively high heterogeneity.[14] Of note, our AARR cutoff of ≥3.7 ng/dL/μU/mL is equivalent to a cutoff of ≥30 ng/dL/ng/ml/h and ≥2.5 ng/dL/pmol/L/min, respectively, for measuring plasma renin activity instead of direct renin concentration.[1] Notably, Vorselaars et al.[10] performed a prospective study in 233 patients with difficult-to-control hypertension who were all referred to a SIT. In that study, the PA prevalence was 6.9% and the sensitivity, specificity, PPV, and NPV for the aldosterone-to-renin activity ratio in detecting PA were 100%, 86.7%, 35.6%, and 100%, respectively.[10] Despite the use of different laboratory methods, these findings are similar to those from the GECOH study.[10]

One major difference between our study and the existing literature is that we performed PA diagnostic testing under ongoing antihypertensive treatment without substantially altering drug intake, except for spironolactone, canrenoate, eplerenone, amiloride, and/or triamterene, which interfere with aldosterone action. We are well aware that several antihypertensive drugs may alter renin concentrations and PAC, but we have shown that AARR measurements performed under standardized conditions (as in the GECOH study) have excellent reproducibility, with very low intraindividual variability.[18] In this context, we found that the second AARR determination did not lead to the diagnosis of any additional PA case that would have been overlooked by just a single AARR determination. We cannot rule out, however, that we missed PA cases because of ongoing drug intake; however, among individuals without PA, the PAC after the SIT did not significantly differ between those with and without a positive baseline AARR. Furthermore, only eight participants with a positive SIT result had a negative AARR and thus were not classified as having PA. These participants were, however, likely to have secondary aldosteronism with relatively high renin concentrations and only slightly elevated post-SIT PAC.

Apart from this, it must be acknowledged that diagnostic studies on PA are, in general, prone to verification bias and are limited because there is no gold standard for the confirmation or exclusion of PA, although there are excellent approaches for standardization.[29] This diagnostic challenge may be attributed to the fact that the association of AARR with blood pressure and cardiovascular risk exists on a continuum.[30] In this context, a recent trial has shown that the blood pressure–lowering effects of spironolactone is linearly associated with the prevailing AARR that was measured, as in the GECOH study, under ongoing antihypertensive treatment.[31] Although it may therefore appear arbitrary to choose an AARR cutoff for PA diagnostics, it has to be stressed that correct diagnosis of PA is pivotal due to highly effective treatment of this disease with either unilateral adrenalectomy or mineralocorticoid receptor blocker therapy resulting in significantly improved overall health outcome.[32] Of note, the six patients with an aldosterone-producing adenoma undergoing unilateral adrenalectomy showed excellent responses to treatment; four of these patients reached normotensive blood pressure without the aid of antihypertensive drugs. For clinical practice, the ARR carries important quantitative information—previous research found that increasing ARR values identifies patients with an exponentially increasing probability of carrying an aldosterone-producing adenoma.[15]

Our data are limited because we studied a cohort of patients referred to a tertiary care center, and therefore we cannot uncritically generalize our results to other populations. In addition, there are no gold standard criteria for the diagnosis of PA; although we strictly adhered to published criteria in terms of assay cutoffs and guideline-recommended case confirmation by the SIT, we cannot rule out some misclassifications. Moreover we could not (mainly because of a lack of funding) analyze some prespecified secondary outcomes. Furthermore, our participants were not willing to stop β-blocker intake; this suggests that at least in our study setting, but probably also in other populations, it may not be possible to perform AARR measurements without potentially interfering drugs, such as e.g. β-blockers or angiotensin-converting enzyme inhibitors. Therefore, we consider it a main strength of our study that we provide data on the diagnostic accuracy of the AARR under ongoing antihypertensive treatment, an approach that is supported by the Endocrine Society clinical practice guideline for the management of PA.[1] Finally, our results confirm some previously published characteristics of patients with PA, such as the high PTH concentrations.[33]

In conclusion, we have documented in the GECOH study that even without significantly altering intake of first-line antihypertensive drug treatment, the AARR has good diagnostic accuracy in detecting PA, as does the SIT. These findings may contribute to a broader implementation of PA diagnostic tests.

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