The Intra-Procedural Cortisol Assay During Adrenal Vein Sampling: Rationale andDesign of A Randomized Study (I-PADUA)

Primary aldosteronism (PA) is a common form of hypertension caused by excess aldosterone secretion: it involves over 11% of the patients referred to specialized hypertension centres [1], about one fifth of those with drug-resistant hypertension [2] and about 6% of the hypertensive patients seen in general practice [3].

PA is held to cause cardiovascular disease in excess of the degree of blood pressure elevation, which translates into a high rate of cardiovascular events. These ominous consequences can be prevented with a timely diagnosis. Once the diagnosis of PA has been made, the decision to proceed further with surgical or medical treatment depends on identification of the PA subtype. In fact, adrenalectomy, can be necessary in up to two thirds of the PA cases [1], and was shown to regress cardiovascular damage and prevent CV events at long-term [4]. Therefore, identification of PA followed by subtyping entails fundamental steps that can be particularly beneficial in some subgroups of patients as those with drug-resistant hypertension, who are at high cardiovascular risk of PA [2].

Adrenalectomy is indicated only once a lateralized aldosterone excess has been identified by adrenal vein sampling (AVS). This is a technically challenging procedure because placing the catheter's tip within the tiny and short right adrenal vein is difficult. Samples are, therefore, often obtained from at or near the orifice of the vein, which can lead to dilution of the adrenal hormones, and thus to non selective studies. Unfortunately, accomplishment bilateral selectivity was disappointingly low, particularly if high cutoff values of the selectivity index are used, as shown by the largest study ever performed worldwide. To overcome this limitation several methods have recently been proposed, including stimulation with cosyntropin or metoclopramide [5-10], use of alternative biomarkers, as for example, plasma metanephrines or androstenedione that have a step-up between adrenal vein and inferior vena cava (IVC) higher than cortisol [11], and the intra-procedural rapid cortisol assay (IRCA). The latter can improve the success rate of AVS, particularly at a stage when radiologists are gaining experience with the procedure. Accordingly, several centres have adopted this practice after its introduction [12] and reported anecdotal successes, but logistic problems have prevented widespread use of IRCA in clinical practice [13].

Recently a kit for the semi-quantitative IRCA has been developed [14], which lends itself to routine clinical use owing to its simplicity, ease, and speed of use. Yet, the advantages of exploiting an IRCA-based strategy for improving the success rate in achieving selectivity of AVS has been proven only in one randomized clinical trial (RCT) carried out in Japan, which involved 7 centres, most of which had no or, a limited experience with AVS [14].

RTCs represent the basis for evidence-based and high-grade class of recommendations in practice guidelines. Therefore, we plan to test the hypothesis that the IRCA during AVS could improve the rate of bilaterally selective AVS studies over that accomplished by a routine AVS protocol even when used at referral centres that routinely perform this diagnostic procedure.