Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

BACKGROUND: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment. METHODS: We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and ß-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated. RESULTS: Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents (P=0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P=0.022) and adrenalectomy (72% versus 54%; P=0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels. CONCLUSIONS: At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Unilaterally Selective Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism but is often clinically useless, owing to failed bilateral adrenal vein cannulation. OBJECTIVES: To investigate if only unilaterally selective adrenal vein sampling studies can allow the identification of the responsible adrenal. METHODS: Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling results in at least one side; we used surgically cured unilateral primary aldosteronism as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined. RESULTS: We found prominent differences in RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under receiver operating characteristic curves was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on the former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism, only 20% and 16% had RASI values ≤0.96 and >2.55. CONCLUSIONS: With the strength of a large real-life data set and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01234220.

Drug-resistant hypertension in primary aldosteronism patients undergoing adrenal vein sampling: the AVIS-2-RH study.

AIMS: We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres. METHODS AND RESULTS: The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all. CONCLUSIONS: (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Pharmacological and safety profile of a prolonged-release lanreotide formulation in acromegaly.

BACKGROUND: Patients with acromegaly require lifelong medication; a longer dosing interval would reduce treatment burden. This study investigated the pharmacokinetics, pharmacodynamics and safety profile of a new prolonged-release formulation (PRF) of lanreotide every 12 weeks. RESEARCH DESIGN AND METHODS: In this multicenter, open-label, dose-ascending study, cohorts of nine patients with acromegaly received single doses of lanreotide PRF according to a 3 + 3 + 3 scheme in order to determine the maximum tolerated dose (MTD). Following a 12-week treatment period, patients were followed up for a further 12 weeks. Serum lanreotide, insulin-like growth factor-1 and growth hormone concentrations were analyzed. Adverse events were monitored throughout the study. RESULTS: The MTD was not reached. Peak lanreotide serum concentration values were similar in all cohorts, whereas area under the curve values from time zero to 85 days increased but were not dose-proportional. The apparent elimination half-life of lanreotide PRF was approximately 54-63 days, in line with the expected prolonged-release characteristics. Growth hormone and insulin-like growth factor-1 levels were generally stable. CONCLUSIONS: The safety and tolerability profile was in-line with the known safety profile of lanreotide autogel. Lanreotide PRF was well tolerated and the pharmacokinetic profile suggests that a dosing interval of 12 weeks could be achievable. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT02396953; EudraCT 2014-002389-62.

Identification of Surgically Curable Primary Aldosteronism by Imaging in a Large, Multiethnic International Study.

CONTEXT: Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy. OBJECTIVE: This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging. METHODS: This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. RESULTS: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. CONCLUSION: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization.

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

Clinical Outcomes of 1625 Patients With Primary Aldosteronism Subtyped With Adrenal Vein Sampling.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.