Horm Metab Res 2015; 47(13): 1000-1006
DOI: 10.1055/s-0035-1565128
Review

Mineralocorticoid Receptor Antagonists and Clinical Outcomes in Primary Aldosteronism: As Good as Surgery?

L. A. Sechi
1   Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
,
G. L. Colussi
1   Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
,
M. Novello
1   Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
,
A. Uzzau
2   General Surgery, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
,
C. Catena
1   Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
› Author Affiliations

Abstract

Primary aldosteronism (PA) is detected with increasing frequency in hypertensive patients and is associated with excess cardiovascular, renal, and metabolic complications. For these reasons, appropriate choices for treatment of this endocrine condition are mandatory. Adrenalectomy is safely performed in PA patients when adrenal venous sampling (AVS) demonstrates lateralized aldosterone secretion. AVS, however, is a complex procedure and even among worldwide referral centers there are substantial discrepancies for interpretation of results. Also, in the majority of PA patients with lateralized aldosterone secretion, hypertension may persist after adrenalectomy requiring use of additional antihypertensive agents. Treatment with mineralocorticoid receptor antagonists (MRAs) is currently recommended for PA patients with bilateral adrenal disease, but these agents effectively decrease blood pressure also in patients with unilateral disease, although concern remains for possible sex-related side effects. Prospective studies indicate that MRAs have therapeutic values comparable to surgery in the long-term, inasmuch as they effectively correct metabolic abnormalities and subclinical organ damage and reduce the risk of cardiovascular events and renal disease progression. This article overviews the clinical outcomes obtained in patients with PA with use of MRAs.



Publication History

Received: 14 August 2015

Accepted: 14 October 2015

Article published online:
14 December 2015

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Sechi LA, Colussi GL, Di Fabio A, Catena C. Cardiovascular and renal damage in primary aldosteronism: outcomes after treatment. Am J Hypertens 2010; 23: 1253-1260
  • 2 Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab 2015; 100: 1-10
  • 3 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr WF, Montori VM. Endocrine Society . Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266-3281
  • 4 Steichen O, Lorthioir A, Zinzindohoue F, Plouin PF, Amar L. Outcomes of drug-based and surgical treatments for primary aldosteronism. Adv Chronic Kidney Dis 2015; 22: 196-203
  • 5 Muth A, Ragnarsson O, Johannsson G, Wangberg B. Systematic review of surgery and outcomes in patients with primary aldosteronism. Br J Surg 2015; 102: 307-317
  • 6 Amar L, Lorthioir A, Azizi M, Plouin PF. Mineralocorticoid antagonist treatment for aldosterone-producing adenoma. Eur J Endocrinol 2015; 172: 125-129
  • 7 Cella J, Brown EA, Burtner RR. Steroidal aldosterone blockers. J Org Chem 1959; 24: 743-748
  • 8 Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Failure Reviews 2005; 10: 23-29
  • 9 Colussi GL, Catena C, Sechi LA. Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension. J Hypertens 2013; 31: 3-15
  • 10 Lowder SC, Liddle GW. Prolonged alteration of renin responsiveness after spironolactone therapy. A cause of false-negative testing for low-renin hypertension. N Engl J Med 1974; 291: 1243-1244
  • 11 Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 2002; 15: 709-716
  • 12 Parthasarathy HK, Ménard J, White WB, Young Jr WF, Williams GH, Williams B, Ruilope LM, McInnes GT, Connell JM, MacDonald TM. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011; 29: 980-990
  • 13 Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio. Circulation 2007; 116: 268-275
  • 14 Kupers EM, Amar L, Raynaud A, Plouin PF, Steichen O. A clinical prediction score to diagnose unilateral primary aldosteronism. J Clin Endocrinol Metab 2012; 97: 3530-3537
  • 15 Mulatero P, Monticone S, Veglio F. Diagnosis and treatment of primary aldosteronism. Rev Endocr Metab Disord 2011; 12: 3-9
  • 16 Rossi GP, Auchus RJ, Brown M, JWM Lenders, Naruse M, Plouin PF, Satoh F, Young WF. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 2014; 63: 151-160
  • 17 Monticone S, Viola A, Rossato D, Veglio F, Reincke M, Gomez-Sanchez C, Mulatero P. Adrenal vein sampling in primary aldosteronism: towards a standardised protocol. Lancet Diabetes Endocrinol 2015; 3: 296-303
  • 18 Vonend O, Ockenfels N, Gao X, Allolio B, Lang K, Mai K, Quack I, Saleh A, Degenhart C, Seufert J, Seiler L, Beuschlein F, Quinkler M, Podrabsky P, Bidlingmaier M, Lorenz R, Reincke M, Rump LC. Adrenal venous sampling. Evaluation of the German Conn’s registry. Hypertension 2011; 57: 990-995
  • 19 Mulatero P, Bertello C, Sukor N, Gordon R, Rossato D, Daunt N, Leggett D, Mengozzi G, Veglio F, Stowasser M. Impact of different diagnostic criteria during adrenal vein sampling on reproducibility of subtype diagnosis in patietns with primary aldosteronism. Hypertension 2010; 55: 667-673
  • 20 Lethielleux G, Amar L, Raynaud A, Plouin PF, Steichen O. Influence of diagnostic criteria in the interpretation of adrenal vein sampling. Hypertension 2015; 65: 849-854
  • 21 Hennings J, Sundin A, Hagg A, Hellman P. 11C-methomidate positron emission tomography after dexamethasone suppression for detection of small adrenocortical adenomas in primary aldosteronism. Langenbecks Arch Surg 2010; 395: 963-967
  • 22 Rutherford JC, Taylor WL, Stowasser M, Gordon RD. Success for surgery for primary aldosteronism judged by residual autonomous aldosterone production. World J Surg 1998; 22: 1243-1245
  • 23 Karagiannis A, Tziomalos K, Kakafika AI, Athyros VG, Harsoulis F, Mikhailidis DP. Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas. Endocr Relat Cancer 2008; 15: 693-700
  • 24 van der Linden P, Steichen O, Zinzindohouè F, Plouin PF. Blood pressure and medication changes following adrenalectomy for unilateral primary aldosteronsim: a follow-up study. J Hypertens 2012; 30: 761-769
  • 25 Catena C, Colussi GL, Di Fabio A, Valeri M, Marzano L, Uzzau A, Sechi LA. Mineralocorticoid antagonist treatment versus surgery in primary aldosteronism. Horm Metab Res 2010; 42: 440-445
  • 26 Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study. Br J Clin Pharmacol 1999; 48: 756-760
  • 27 Karagiannis A, Tziomalos K, Papageorgiou A, Kakafika AI, Pagourelias ED, Anagnostis P, Athyros VG, Mikhailidis DP. Spironolactone versus eplerenone for the treatment of primary aldosteronism. Expert Opin Parmacother 2008; 9: 509-515
  • 28 Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med 2008; 168: 80-85
  • 29 Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F, Pessina AC. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension 2013; 62: 62-69
  • 30 Zacharieva S, Orbetzova M, Elenkova AS, Stoynev A, Yaneva M, Schigarminova R, Kalinov K, Nachev E. Diurnal blood pressure pattern in patients with primary aldosteronism. J Endocrinol Invest 2006; 29: 26-31
  • 31 Sechi LA, Di Fabio A, Bazzocchi M, Uzzau A, Catena C. Intrarenal hemodynamics in primary aldosteronism before and after treatment. J Clin Endocrinol Metab 2009; 94: 1191-1197
  • 32 Hanusch FM, Fischer E, Lang K, Diederich S, Endres S, Allolio B, Beuschlein F, Reincke M, Quinkler M. Sleep quality in patients with primary aldosteronism. Hormones 2014; 13: 57-64
  • 33 Kline GA, Pasieka JL, Harvey A, So B, Dias VC. Medical or surgical therapy for primary aldosteronism: post-treatment follow-up as a surrogate measure of comparative outcomes. Ann Surg Oncol 2013; 20: 2274-2278
  • 34 Giacchetti G, Ronconi V, Turchi F, Agostinelli L, Mantero F, Rilli S, Boscaro M. Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study. J Hypertens 2007; 25: 177-186
  • 35 Fourkiotis V, Vonend O, Diederich S, Fischer E, Lang K, Endres S, Beuschelein F, Willemberg HS, Rump LC, Allolio B, Reincke M, Quinkler M. Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism. Eur J Endocrinol 2013; 168: 75-81
  • 36 Iwakura Y, Morimoto R, Kudo M, Ono Y, Takase K, Seiji K, Arai Y, Nakamura Y, Sasano H, Ito S, Satoh F. Predictors of decreasing glomerular filtration rate and prevalence of chronic kidney disease after treatment of primary aldosteronism: renal outcome of 213 cases. J Clin Endocrinol Metab 2014; 99: 1593-1598
  • 37 Ahmed AH, Gordon RD, Sukor N, Pimenta E, Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including comparison with our previously published results in those with unilateral disease treated surgically. J Clin Endocrinol Metab 2011; 96: 2904-2911
  • 38 Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, Crudo V, Burrello J, Milan A, Rabbia F, Veglio F. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab 2013; 98: 4826-4833
  • 39 Miyake Y, Tanaka K, Nishikawa T, Naruse M, Takayanagi R, Sasano H, Takeda Y, Shibata H, Sone M, Satoh F, Yamada M, Ueshiba H, Katabami T, Iwasaki Y, Tanaka H, Tanahashi Y, Suzuki S, Hasegawa T, Katsumata N, Tajima T, Yanase T. Prognosis of primary aldosteronism in Japan: results from a nationwide epidemiological study. Endocr J 2014; 61: 35-40
  • 40 Rossi GP, Pessina AC, Heagerty AM. Primary aldosteronism: an update on screening, diagnosis and treatment. J Hypertens 2008; 26: 613-621
  • 41 Kaplan NM. Primary aldosteronism: an update on screening, diagnosis and treatment. J Hypertens 2008; 26: 1708-1709 author reply 1709
  • 42 Douma S, Petiddis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopulos N, Vogiatzis K, Zamboulis C. Prevalence of primary aldosteronism in resistant hypertension: a retrospective observational study. Lancet 2008; 371: 1921-1926
  • 43 Stowasser M. Adrenal venous sampling for differentiating unilateral from bilateral primary aldosteronism. Still the best but could be better. Hypertension 2015; 65: 704-706
  • 44 Brown JJ, Davies Dl, Ferriss JB, Fraser R, Haywood E, Lever AF, Robertson JIS. Comparison of surgery or prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin. Br Med J 1972; 2: 729-734
  • 45 Kater CE, Biglieri EG, Schambelan M, Arteaga E. Studies of impaired aldosterone response to spironolactone-induced renin and potassium elevations in adenomatous but not hyperplastic primary aldosteronism. Hypertension 1983; 5 suppl V 115-121
  • 46 Ghose RP, Hall PM, Bravo EL. Medical management of aldosterone-producing adenomas. Ann Intern Med 1999; 1331: 105-108
  • 47 Rossi GP, Sechi LA, Giacchetti G, Ronconi V, Strazzullo P, Funder LW. Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab 2008; 19: 88-90
  • 48 Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism. Hypertension 2013; 62: 331-336
  • 49 Catena C, Colussi GL, Nait F, Martinis F, Pezzutto F, Sechi LA. Front Endocrinol 2014; 5: 168
  • 50 Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mannelli M, Matterello MJ, Montemurro D, Palumbo G, Rizzoni D, Rossi E, Pessina AC, Mantero F. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension 2006; 48: 232-238
  • 51 Reincke M, Rump LC, Quinkler M, Hahner S, Diederich S, Lorenz R, Seufert J, Schirpenbach C, Beuschlein F, Bidlingmaier M, Meisinger C, Holle R, Endres S. Participants of German Conn’s Registry . Risk factors associated with a low glomerular filtration rate in primary aldosteronism. J Clin Endocrinol Metab 2009; 94: 869-875
  • 52 Sechi LA, Catena C. The dual role of the kidney in primary aldosteronism: key determinant in rescue from volume expansion and persistence of hypertension. Am J Kidney Dis 2009; 54: 594-597
  • 53 Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, Rabbia F, Federspil G, Mulatero P. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 2006; 91: 454-459
  • 54 Sechi LA, Colussi GL, Catena C. Role of aldosterone in insulin resistance: fact or fantasy. Endocrinol Metab Synd 2015; 4: 1
  • 55 Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Catena C. Long-term renal outcomes in patients with primary aldosteronism. JAMA 2006; 295: 2638-2645
  • 56 Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Relationships of plasma renin levels with renal function in patients with primary aldosteronism. Clin J Am Soc Nephrol 2007; 2: 722-731
  • 57 Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Palluf A, Quinkler M, Hanslik G, Lang K, Hahner S, Allolio B, Meisinger C, Holle R, Beuschelein F, Bidlingmaier M, Endres S. Observational study mortality in treated primary aldosteronism: the German Conn’s Registry. Hypertension 2012; 60: 618-624
  • 58 Muiesan ML, Salvetti M, Paini A, Agabiti-Rosei C, Monteduro C, Galbassini G, Belotti E, Aggiusti C, Rizzoni D, Castellano M, Agabiti-Rosei E. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension 2008; 52: 529-534
  • 59 Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P, Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007; 50: 911-918
  • 60 Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F, Pessina AC. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension 2013; 62: 62-69
  • 61 Bernini G, Bacca A, Carli V, Carrara D, Materazzi G, Berti P, Miccoli P, Pisano R, Tantardini V, Bernini M, Taddei S. Cardiovascular changes in patients with primary aldosteronism after surgical or medical treatment. J Endocr Invest 2012; 35: 274-280
  • 62 Catena C, Colussi GL, Marzano L, Sechi LA. Predictive factors of left ventricular mass changes after treatment of primary aldosteronism. Horm Metab Res 2012; 44: 188-193
  • 63 Marzano L, Colussi GL, Sechi LA, Catena C. Adrenalectomy is comparable to medical treatment for reduction of left ventricular mass in primary aldosteronism: meta-analysis of long-term studies. Am J Hypertens 2015; 28: 312-318
  • 64 Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, Lang K, Quack I, Rump LC, Willenberg HS, Beuschlein F, Quinkler M, Hannemann A. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn registry. Eur J Endocrinol 2015; 173: 665-675
  • 65 Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab 2007; 91: 3457-3463
  • 66 Sukor N, Kogovsek C, Gordon RD, Robson D, Stowasser M. Improved quality of life, blood pressure, and biochemical status following laparoscopic adrenalectomy for unilateral primary aldosteronism. J Clin Endocrinol Metab 2010; 95: 1360-1364
  • 67 Kunzel HE, ApostolopoulouK Pallauf A, Gerum S, Merkle K, Schulz S, Fischer E, Brand V, Bidlingmaier M, Endres S, Beuschelein F, Reincke M. Quality of life in patients with primary aldosteronism: gender differences in untreated and long-term treated patients and associations with treatment and aldosterone. Eur J Endocrinol 2012; 46: 1650-1654
  • 68 Dietz JD, Du S, Bolten CW, Payne MA, Xia C, Blinn JR, Funder JW, Hu X. A number of marketed dihydropyridine calcium channel blockers have mineralocorticoid receptor antagonist activity. Hypertension 2008; 51: 742-748
  • 69 Fagart J, Hillisch A, Huyet J, Bärfacker L, Fay M, Pleiss U, Pook E, Schäfer S, Rafestin-Oblin M-E, Kolkhof P. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem 2010; 285: 29932-29940
  • 70 Jansen PM, van der Meiracker AH, Danser JAH. Aldosterone synthase inhibitors: pharmacological and clinical aspects. Curr Opin Investig Drugs 2009; 10: 319-326
  • 71 Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Ménard J. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 2011; 124: 1945-1955
  • 72 Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin P-F. Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 2010; 56: 831-838
  • 73 Amar L, Azizi M, Menard J, Peyrard S, Plouin PF. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J Hypertens 2013; 31: 624-629