Exclusion Tests in Unilateral Primary Aldosteronism (ExcluPA) Study

Abstract

Importance Determining the diagnostic accuracy of “exclusion” tests for primary aldosteronism (PA) compared to the aldosterone-to-renin ratio (ARR) is fundamental to avoid invasive subtyping in false-positive patients at screening. Objective To assess the accuracy of exclusion tests for PA using the diagnosis of unilateral PA as reference. Data Sources PubMed, EMBASE, Web of Science and Cochrane Library databases. Study Selection Studies that met tight quality criteria published from January 1st, 1970 to December 31st, 2021. Data Extraction and Synthesis Data were extracted following the PRISMA methodology. We performed a two-stage meta-analysis that entailed an exploratory and a validation phase based on a “golden” or “gold” diagnostic standard, respectively. Pooled specificity, negative likelihood ratio, diagnostic odds ratio, and summary area under the ROC curve (sAUROC) were calculated. Main Outcome and Measure The accuracy of exclusion tests. Findings 31 datasets comprising a total of 4,242 patients fulfilling the predefined inclusion criteria were meta-analyzed. Pooled accuracy estimates (sAUROC) did not differ between the ARR (0.95, 95% CI: 0.92-0.98), the captopril challenge test (CCT) (0.92, 95% CI: 0.88-0.97), and the saline infusion test (SIT) (0.96, 95% CI: 0.94-0.99). Solid information could not be obtained for the fludrocortisone suppression test and the furosemide upright test, which were assessed in only one study each. Conclusions and Relevance The apparently high diagnostic accuracy of the CCT and the SIT was due to the selection of patients with an elevated ARR and thus a high pre-test probability of unilateral PA; however, neither test furnished a diagnostic gain over the ARR. Therefore, the systematic use of these exclusion tests in clinical practice is not justified by available evidence.

The Spectrum from Overt Primary Aldosteronism to Mild Dysregulated Aldosterone Production in Incidentally Discovered Adrenocortical Adenomas

“…This was achieved even without the use of confirmatory testing, which might have reduced the number of patients who could potentially benefit from targeted therapy due to stricter thresholds. 3,38,39 Additionally, PAC was measured using immunoassay, which has known limitations compared to LC-MS/MS, 40 however, urinary aldosterone was measured using LC-MS/MS, and the results behaved similarly.…”

Captopril challenge test: an underutilized test in the diagnosis of primary aldosteronism

“…Of all the studies that evaluated the CCT, the PAPY ( 26 ) and CONPASS ( 31 ) studies were prospectively conducted with rigorous criteria and a large number of subjects. Both studies administered a 50 mg oral dose of captopril and measured aldosterone and renin concentrations with either radioimmunoassay (PAPY study) or automated chemiluminescence immunoassays (CONPASS study) ( 18 , 19 ). The outcome measure of aldosterone concentration ( 29 , 34 , 35 ) provided greater diagnostic accuracy than the ARR ( 43 , 46 , 47 ) at 2 h post captopril.…”

“…It is important to confirm an elevated ARR with additional testing unless the patient has florid biochemical features of PA including suppressed renin, high aldosterone concentration, and hypokalemia. Indeed, a recent meta-analysis of 31 datasets comprising 4242 patients found that pooled accuracy estimates (summary area under the operating characteristics curve (sAUROC)) did not differ between the screening ARR (0.95; 95% CI 0.92–0.98), CCT (0.92; 95% CI 0.88–0.97), and SST (0.96; 95% CI 0.94–0.99) for the diagnosis of unilateral PA, possibly due to their florid presentations ( 18 ).…”

Primary Aldosteronism and Drug Resistant Hypertension: A “Chicken-Egg” Story

“…The scientific evidence supporting the usefulness of these tests is very weak. In fact, two large independent meta-analyses of the studies with the more solid design concluded that they are unreliable, not adequately validated and, therefore, should not be performed [52,53]. Moreover, these tests, which are based on the premise that aldosterone-secreting tissues in PA are autonomous from angiotensin II [54], a totally unproven hypothesis, cause special problems in patients with RH, who, by definition, are on multiple drugs interfering with angiotensin II formation or action.…”