Study on Cutoff Revision Effects and Evaluation of NNT in Primary Aldosteronism

Primary aldosteronism (PA) is one of the most common causes of secondary hypertension and is associated with an increased risk of cardiovascular, renal, and metabolic complications independent of blood pressure levels. Despite its clinical importance and the availability of effective targeted treatments such as adrenalectomy or mineralocorticoid receptor antagonists, PA remains substantially underdiagnosed in routine clinical practice, with estimates suggesting that only a small proportion of eligible hypertensive patients undergo appropriate screening.

The aldosterone-to-renin ratio (ARR) is the most widely used screening tool for PA. Traditionally, an ARR cutoff of >30 has been used to define a positive screening result. However, recent evidence suggests that this threshold may lack sufficient sensitivity and may miss a considerable number of patients with clinically relevant PA. In response, recent international hypertension and endocrine society guidelines have proposed lowering the ARR cutoff to >20 in order to improve case detection and broaden screening indications.

However, lowering the ARR threshold may also increase the number of false-positive results, potentially leading to an increased burden of aldosterone suppression test. Therefore, the clinical utility of the revised cutoff must be evaluated in real-world settings, particularly with regard to diagnostic yield and testing efficiency.

This study is a multicenter, prospective observational cohort study designed to evaluate the impact of applying the revised ARR cutoff (>20) in routine clinical practice in Korea. Patients with hypertension who meet predefined biochemical screening criteria indicating an intermediate probability of lateralizing PA will be enrolled.

Participants will undergo standardized pre-analytical preparation, including medication adjustment and controlled sampling conditions. All eligible participants will undergo confirmatory testing using the saline infusion test (SIT), performed under standardized protocols (supine or seated depending on institutional practice).

The primary objective of this study is to determine the number of confirmatory tests required to diagnose one case of PA (number needed to test, NNT) when using the revised ARR cutoff (>20). Secondary outcomes include biochemical treatment response at 6 months (complete biochemical success), and identification of an optimal ARR cutoff value using receiver operating characteristic (ROC) analysis.

The findings of this study are expected to provide real-world evidence regarding the diagnostic efficiency and clinical implications of lowering the ARR cutoff in Korean patients, and may inform future guideline updates and clinical decision-making strategies for the screening and diagnosis of primary aldosteronism.

Inclusion criteria

• Adults aged 18 years or older
• Diagnosis of hypertension or current use of antihypertensive medications
• Plasma renin activity (PRA) ≤1 ng/mL/hr
• Plasma aldosterone concentration (PAC) ≥10 ng/dL by immunoassay or ≥7.5 ng/dL by liquid chromatography-tandem mass spectrometry (LC-MS/MS)
• Aldosterone-to-renin ratio (ARR) >20 by immunoassay or >15 by LC-MS/MS
• Participants meeting criteria for intermediate probability of lateralizing primary aldosteronism
• For participants with ARR values between 20 and 30, repeat ARR measurement within 26 weeks demonstrating persistent ARR >20

Exclusion criteria

• Current use of mineralocorticoid receptor antagonists or amiloride that cannot be discontinued according to study protocol
• Previous adrenalectomy
• Chronic kidney disease stage 4 or higher (estimated glomerular filtration rate <30 mL/min/1.73 m²)
• Pregnancy
• Current use of combined estrogen- and progesterone-containing oral contraceptive pills or hormone replacement therapy
• High probability primary aldosteronism defined as hypokalemia with PRA <0.2 ng/mL/hr and PAC >20 ng/dL by immunoassay or >15 ng/dL by LC-MS/MS
• Low probability primary aldosteronism defined as PAC <11 ng/dL by immunoassay or <8 ng/dL by LC-MS/MS
• Inability to undergo saline infusion test according to investigator judgment