Adrenal Venous Sampling Versus Computed Tomographic Scan to Determine Treatment in Primary Aldosteronism (The SPARTACUS Trial)
2017; Lippincott Williams & Wilkins; Volume: 69; Issue: 3 Linguagem: Inglês
10.1161/hypertensionaha.116.08820
ISSN1524-4563
AutoresGian Paolo Rossi, John W. Funder,
Tópico(s)Adrenal Hormones and Disorders
ResumoHomeHypertensionVol. 69, No. 3Adrenal Venous Sampling Versus Computed Tomographic Scan to Determine Treatment in Primary Aldosteronism (The SPARTACUS Trial) Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAdrenal Venous Sampling Versus Computed Tomographic Scan to Determine Treatment in Primary Aldosteronism (The SPARTACUS Trial)A Critique Gian Paolo Rossi and John W. Funder Gian Paolo RossiGian Paolo Rossi From the Clinica dell'Ipertensione Arteriosa and Department of Medicine, DIMED, University of Padova, Italy (G.P.R.); and Department of Steroid Biology, Hudson Institute, Monash Medical Centre, Clayton, Victoria, Australia (J.W.F.). and John W. FunderJohn W. Funder From the Clinica dell'Ipertensione Arteriosa and Department of Medicine, DIMED, University of Padova, Italy (G.P.R.); and Department of Steroid Biology, Hudson Institute, Monash Medical Centre, Clayton, Victoria, Australia (J.W.F.). Originally published30 Jan 2017https://doi.org/10.1161/HYPERTENSIONAHA.116.08820Hypertension. 2017;69:396–397Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 In patients confirmed to have primary aldosteronism (PA), routine adrenal venous sampling (AVS) is recommended by the current international guidelines1,2 with 2 caveats. The first is in patients unable or unwilling to undergo surgery, the treatment of choice for unilateral disease, most commonly an aldosterone-producing adenoma (APA). The second exception can be for young patients with undetectable plasma renin, very high plasma aldosterone concentration, profound hypokalemia, and a unilateral adenoma on imaging as illustrated in the flow chart in the recent Endocrine Society guideline.2AVS is technically demanding, with catheterization requiring a dedicated interventionist, usually a radiologist; in addition, interpretation of the results similarly requires experience.3 The procedure is thus not widely available, despite its being safe and minimally invasive, and is in both private and public health systems relatively expensive.4 Given those issues, it is not surprising that currently there are many studies directed at reducing the need for AVS to a gray zone, by measurement in peripheral plasma of markers with high levels strongly indicative of a unilateral cause, mostly an APA, and low levels of bilateral adrenal hyperplasia.3This incrementalist approach was not that taken by Dekkers et al5 in the recent SPARTACUS trial (Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan). There is clear consensus that all patients confirmed positive for PA should undergo imaging, preferably by computed tomography (CT), ostensibly to exclude carcinoma, practically offering some guide to the interventionist.2,3 SPARTACUS recruited 200 patients with florid PA, of whom 184 completed follow-up and were randomly assigned to 2 groups of 92, to have lateralization decided by CT alone or by AVS (post-CT). In both groups, 46 patients were adjudged to have unilateral disease, a symmetry that goes unremarked, and underwent laparoscopic adrenalectomyPatients were followed up for a year, and their daily defined dose regime post-operatively used as a measure of successful outcome in each group.No significant differences in daily defined dose, median RAND-36 physical or mental scores,6 or reaching target blood pressure, were found between the groups; a nonsignificant mean difference in favor of AVS was found for quality-adjusted life years; 5 AVS patients and 9 CT-alone patients had persistent hyperaldosteronism. The interpretation of those findings was "Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism."2Both of these sentences are open to substantial dispute, on an unusually broad range of issues. In order,The cohort studied is not representative of PA: Only 50 of the 184 patients studied were women, a clear distortion and evidence of substantial referral bias. The patients were admitted on the basis of either drug-resistant hypertension or hypokalemia, spontaneous or diuretic induced. Resistant hypertension has a high incidence of PA (15%–20%); hypokalemia is found in ≈50% of patients with APA and ≈20% of those with bilateral adrenal hyperplasia.2 Patients with florid PA are known to have more marked target organ damage, including left ventricular hypertrophy, renal damage, and vascular remodeling, which predict persistence of high blood pressure after adrenalectomy7; accordingly, they are less likely to achieve remission of hypertension—with either surgical or medical treatment—so that the possibility of finding a difference between cohorts is slim. Moreover, patients were included if they had "clinically suspected primary aldosteronism as underlying cause of hypertension confirmed by a salt-loading test." This may lead to the exclusion of those patients (up to 71%), who have angiotensin II–responsive APA.7 Therefore, the choice of such a cohort makes it not possible to generalize the SPARTACUS findings to "all patients with primary aldosteronism."End points, sample size, and intention-to-diagnose analysis: The choice of primary end point (daily defined dose 1 year post-intervention) is suboptimal as an outcome measure inasmuch as AVS is not recommended to lower the intensity of drug treatment necessary for obtaining target blood pressure, but rather to cure patients from PA with adrenalectomy. A finer-grained analysis would have compared biochemical resolution in terms of correction of hypokalemia, and a rise in renin/fall in aldosterone into the normal range as primary end points, plus levels of complete remission of hypertension/partial remission/no change, or increase, as clinical end points. The authors calculated the sample size to achieve 80% power to detect a difference in daily defined dose between groups, assuming a 1.8 SD, which required 81 patients per arm for a 2-sided α=0.05. Because their patients went into subgroups of 46 (in medical and surgical arms), only 46 patients underwent adrenalectomy in both arms. With this reduced sample size the power of the study was reduced to ≈50%, eg, equivalent to tossing a coin.The SPARTACUS investigators analyzed their results by the original assignment to a CT-alone or plus AVS diagnostic strategy. What this entailed was that 4 patients with a failed AVS underwent surgery with no independent evidence for a potential benefit, a treatment decision taken on the basis of a previous CT. Notwithstanding this, they remained in the AVS group, which is not easily justified on intention-to-treat grounds. As the authors note, a post hoc analysis, per protocol (ie, after excluding the AVS failures) did not change their conclusion, entirely predictable in that both studies were underpowered.The use of cosyntropin: Cosyntropin is used to increase the adrenal venous blood cortisol levels well over those in the inferior vena cava, facilitating selectivity of catheterization. Unfortunately, given the molecular heterogeneity of aldosterone secretory cells, such stimulation has been found to confound or even invert lateralization,8,9 leading to wrong-sided adrenalectomy in up to 30%, worst case. The authors rightly acknowledge that their results apply only to AVS under cosyntropin. Hence, their findings clearly cannot be extrapolated to unstimulated AVS, which given the problems with cosyntropin clearly should be the choice of preference.Other issues: Although the primary end point was intensity of drug treatment for obtaining target blood pressure after a year of follow-up, only 40% to 46% of patients across the various treatment groups attained target ambulatory blood pressure. The CT findings (left side 38 APA and right side 12 APA) are in clear contrast with the findings on AVS (right side 22 and left side 26). In addition, confidence in CT findings is not helped by the report of discordant conclusions between central and local reading in 14 patients. The antihypertensive regime that the authors chose is not one that would sit comfortably or be adopted in most institutions, and would appear to explain the number of adverse events reported.ConclusionWe welcome any attempt to minimize the necessity of AVS, given its cost and complexity; in this, we are in complete agreement with the SPARTACUS authors. Clinical trials are commonly less than perfect, particularly when conducted between centers and in different countries. The authors have clearly set out the difficulties they faced, and in addition acknowledged that with higher patient numbers, the trends favoring PA they noticed may become significant differences. Similarly, in their defense, it is crucial that all clinical trials—positive, negative, or equivocal—are presented and published, and not allowed to lapse. That said, if a trial has the range of limitations that we have described, it is crucial that the results are conservatively discussed and any conclusions very carefully drawn. The authors are thus correct to write that (in their hands) "Treatment of Primary Aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after one year of follow-up." The limitations of the trial under review, however, make it inappropriate as a basis for generalization and cannot justify the sentence that followed "This finding challenges the current recommendation to perform AVS on all patients with Primary Aldosteronism."Sources of FundingThis study was supported by the COST BM1301–Aldosterone and Mineralocorticoid Receptor EU program (to G.P. Rossi) and by The Foundation for Advanced Research in Hypertension and Cardiovascular Disease to G.P. Rossi, and by The Victorian Government's Operational Infrastructure Support Program to J.W. Funder.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Gian Paolo Rossi, Department of Medicine, DIMED – Internal Medicine 4, University Hospital, Via Giustiniani, 2, 35126 Padova, Italy. E-mail [email protected]References1. Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A; Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism–the Japan Endocrine Society 2009.Endocr J. 2011; 58:711–721.CrossrefMedlineGoogle Scholar2. 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Araujo-Castro M, Paja Fano M, González Boillos M, Pla Peris B, Pascual-Corrales E, García Cano A, Parra Ramírez P, Rojas-Marcos P, Ruiz-Sanchez J, Vicente Delgado A, Gómez Hoyos E, Ferreira R, García Sanz I, Recasens Sala M, Barahona San Millan R, Picón César M, Díaz Guardiola P, García González J, Perdomo C, Manjón Miguélez L, García Centeno R, Percovich J, Rebollo Román Á, Gracia Gimeno P, Robles Lázaro C, Morales-Ruiz M and Hanzu F (2022) Adrenal venous sampling in primary aldosteronism: Experience of a Spanish multicentric study (Results from the SPAIN-ALDO Register), Endocrine, 10.1007/s12020-022-03122-8 Buffolo F, Monticone S, Williams T, Rossato D, Burrello J, Tetti M, Veglio F and Mulatero P (2017) Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?, International Journal of Molecular Sciences, 10.3390/ijms18040848, 18:4, (848) March 2017Vol 69, Issue 3 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.116.08820PMID: 28137983 Originally publishedJanuary 30, 2017 PDF download Advertisement SubjectsClinical StudiesComputerized Tomography (CT)Hypertension
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