Prospective Study on Primary Aldosteronism in Resistant Hypertension (PrePARe)

Prospective Cross-sectional Study on Prevalence of Primary Aldosteronism in Resistant Hypertension and Association With Cardiometabolic Complications

Prevalence of primary aldosteronism (PA) in resistant hypertension is not clear. In addition, emerging evidence supports the role of elevated serum aldosterone in promoting cardiovascular disease, independently from high blood pressure (BP) levels, but current data on this issue are heterogeneous.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Primary Aldosteronism; Resistant Hypertension; Refractory Hypertension; Hypertensive End-Organ Damage; Aortic Ectasia

Detailed Description

PA is the most frequent form of secondary hypertension, with a prevalence that increases with the severity of hypertension. The wide variation of the reported PA prevalence is due to different study design and population. Very few data derive from well designed prospective study. Additional problems in the interpretation of study results are the different diagnostic cut-off used in various centers and the low diffusion of the adrenal vein sampling, that has a central role in the PA diagnosis.

Resistant hypertension (RH) is a condition of insufficient BP control, despite appropriate lifestyle measures and treatment with at least 3 drugs at full dose, including a diuretic, in patients whose adherence to therapy has been confirmed. The primary aim of our study is define prospectively the prevalence of PA in RH.

Moreover, emerging evidence supports the crucial role of elevated serum aldosterone in promoting cardiovascular disease, independently from high BP levels. Aldosterone improves oxidative stress, inflammation, impairs insulin metabolic signaling, reduced endothelial-mediated vasorelaxation and is associated to cardiovascular and renal abnormalities. However, current data on the contribution of PA on cardiometabolic complications have heterogeneous results.

The secondary outcome of our study is to investigate prospectively the association of PA with cardiometabolic complications in a cohort of patients with RH.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Mauro M Maccario, MD; Phone Number: 00390116709559; Email: mauro.maccario@unito.it
• Study Contact Backup: Name: Chiara C Lopez, MD; Phone Number: 00390116335544/5527; Email: chiara.lopez@unito.it

Study Locations

• Italy
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • Recruiting
      • Division of Endocrinology, Diabetology and Metabolism; University of Turin
      • Contact: Mauro M Maccario, MD; Phone Number: 00390116709559; Email: mauro.maccario@unito.it
      • Contact: Mirko M Parasiliti Caprino, MD, PhD; Phone Number: 00390116335544/5527; Email: mirko.parasiliticaprino@unito.it
      • Principal Investigator: Mauro M Maccario, MD
      • Sub-Investigator: Mirko M Parasiliti Caprino, MD, PhD
      • Sub-Investigator: Chiara C Lopez, MD
      • Sub-Investigator: Ezio E Ghigo, MD
      • Sub-Investigator: Nunzia N Prencipe, MD
      • Sub-Investigator: Andrea A Benso, MD, PhD
      • Sub-Investigator: Martina M Bollati, MD
      • Sub-Investigator: Filippo F Egalini, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

At least 100 consecutive patients with age over 18 and under 80 years old and resistant hypertension (defined as uncontrolled blood pressure despite the use of at least 3 antihypertensive drugs at full dose, including a diuretic) referred to the center for diagnosis and treatment of Hypertension (Division of Endocrinology, Diabetology and Metabolism, University of Turin) between March 2011 and July 2020.

Description

Inclusion Criteria:

• age over 18 and under 80 years old;
• diagnosis of resistant hypertension defined as: uncontrolled blood pressure at ambulatory blood pressure measurement (ABPM), despite the use of at least 3 antihypertensive drugs at full dose, including a diuretic.

Exclusion Criteria:

• age under 18 or over 80 years old;
• pseudo-resistant hypertension (poor medication adherence, high salt intake);
• previous cardiovascular disease;
• insulin treated diabetes mellitus;
• other than primary aldosteronism cause of secondary hypertension (obstructive sleep apnea, renal artery stenosis, pheochromocytoma/paraganglioma, primary hyperparathyroidism, autonomous cortisol secretion or over hypercortisolism);
• liver cirrhosis;
• chronic heart failure;
• known malignant neoplasm;
• chronic disease with major organ involvement;
• excessive alcohol ingestion;
• current steroids assumption;
• use of sympathomimetic drugs;
• use of contraceptives.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of diagnosis (prevalence) of primary aldosteronism in prospective cohort of patients with resistant hypertension.	Basal Aldosterone (pg/mL) at baseline.	Baseline.
Number of diagnosis (prevalence) of primary aldosteronism in prospective cohort of patients with resistant hypertension.	Basal Plasma Renin Activity (PRA, ng/mL/h) at baseline.	Baseline.
Number of diagnosis (prevalence) of primary aldosteronism in prospective cohort of patients with resistant hypertension.	Aldosterone (pg/mL) post saline infusion test, performed at baseline.	Baseline.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular hypertrophy in primary aldosteronism and essential resistant hypertension	Left ventricular mass evaluation with Echocardiogram at baseline.	Baseline.
Microalbuminuria in primary aldosteronism and essential resistant hypertension.	Albuminuria/Creatininuria ratio (mg/mmoL) at baseline.	Baseline.
Intima media thickness > 0.9 mm rate in primary aldosteronism versus essential resistant hypertension.	Intima media thickness values (mm) evaluation with carotid Doppler ultrasound at baseline.	Baseline
Chronic kidney disease in primary aldosteronism versus essential resistant hypertension.	Serum creatinine (mg/dL) at baseline.	Baseline.
Aortic ectasia in primary aldosteronism versus essential resistant hypertension.	Aortic size (mm) determined with echocardiogram at baseline.	Baseline.
Atrial fibrillation in primary aldosteronism versus essential resistant hypertension.	Electrocardiogram (ECG) at baseline.	Baseline.
Insulin resistance in primary aldosteronism versus essential resistant hypertension.	Oral glucose tolerance test (OGTT) for determination of glucose (mg/dL) at time 0', 30', 60', 90' and 120' at baseline.	Baseline
Insulin resistance in primary aldosteronism versus essential resistant hypertension.	Oral glucose tolerance test (OGTT) for determination of insulin (mg/dL) at time 0', 30', 60', 90' and 120' at baseline.	Baseline.
Diabetes mellitus rate in primary aldosteronism versus essential resistant hypertension.	Oral glucose tolerance test (OGTT) for determination of glucose (mg/dL) at time 0' and 120' at baseline.	Baseline.
Diabetes mellitus rate in primary aldosteronism versus essential resistant hypertension.	HbA1c (mmol/mol) at baseline.	Baseline.
Sodium levels in primary aldosteronism versus essential resistant hypertension.	Serum Sodium (mmol/L) at baseline.	Baseline.
Potassium levels in primary aldosteronism versus essential resistant hypertension.	Serum Potassium (mmol/L) at baseline.	Baseline.
Oxidative stress in primary aldosteronism versus essential resistant hypertension.	Blood determination of 8-isoprostane (UI/L) at baseline.	Baseline.
Oxidative stress in primary aldosteronism versus essential resistant hypertension.	Blood determination of total antioxidant capacity (UI/L) at baseline.	Baseline.
Dyslipidemia in primary aldosteronism versus essential resistant hypertension.	Serum triglycerides (mg/dL) at baseline.	Baseline.
Dyslipidemia in primary aldosteronism versus essential resistant hypertension.	Serum total-Cholesterol (mg/dL) at baseline.	Baseline.
Dyslipidemia in primary aldosteronism versus essential resistant hypertension.	Serum HDL-Cholesterol (mg/dL) at baseline.	Baseline.
Dyslipidemia in primary aldosteronism versus essential resistant hypertension.	Serum LDL-Cholesterol (mg/dL) at baseline.	Baseline.

Collaborators and Investigators

• Sponsor: University of Turin, Italy
• Investigators: Principal Investigator: Mauro M Maccario, MD, Endocrinology, Diabetology and Metabolism; University of Turin; Study Chair: Ezio E Ghigo, MD, Endocrinology, Diabetology and Metabolism; University of Turin

Publications and helpful links

General Publications

• Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 May;101(5):1889-916. doi: 10.1210/jc.2015-4061. Epub 2016 Mar 2.
• Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA, Rabbia F, Veglio F, Mulatero P. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017 Apr 11;69(14):1811-1820. doi: 10.1016/j.jacc.2017.01.052.
• Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006 Dec 5;48(11):2293-300. doi: 10.1016/j.jacc.2006.07.059. Epub 2006 Nov 13.
• Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004 Mar;89(3):1045-50. doi: 10.1210/jc.2003-031337.
• Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002 Dec;40(6):892-6. doi: 10.1161/01.hyp.0000040261.30455.b6.
• Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky J Jr. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens. 2003 May;17(5):349-52. doi: 10.1038/sj.jhh.1001554.
• Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens. 2004 Nov;22(11):2217-26. doi: 10.1097/00004872-200411000-00026.
• Chandran P. Resistant or difficult-to-control hypertension. N Engl J Med. 2006 Nov 2;355(18):1934; author reply 1934. doi: 10.1056/NEJMc062276. No abstract available.
• Schmidt BM, Schmieder RE. Aldosterone-induced cardiac damage: focus on blood pressure independent effects. Am J Hypertens. 2003 Jan;16(1):80-6. doi: 10.1016/s0895-7061(02)03199-0.
• 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 Feb;91(2):454-9. doi: 10.1210/jc.2005-1733. Epub 2005 Nov 15.
• Rossi GP, Sechi LA, Giacchetti G, Ronconi V, Strazzullo P, Funder JW. Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab. 2008 Apr;19(3):88-90. doi: 10.1016/j.tem.2008.01.006. Epub 2008 Mar 7.
• Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis. 2010 Mar-Apr;52(5):401-9. doi: 10.1016/j.pcad.2009.12.004.
• Fiebeler A, Luft FC. The mineralocorticoid receptor and oxidative stress. Heart Fail Rev. 2005 Jan;10(1):47-52. doi: 10.1007/s10741-005-2348-y.
• Vogt B, Burnier M. Aldosterone and cardiovascular risk. Curr Hypertens Rep. 2009 Dec;11(6):450-5. doi: 10.1007/s11906-009-0076-8.
• Morrow JD. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):279-86. doi: 10.1161/01.ATV.0000152605.64964.c0. Epub 2004 Dec 9.
• Prior RL, Cao G. In vivo total antioxidant capacity: comparison of different analytical methods. Free Radic Biol Med. 1999 Dec;27(11-12):1173-81. doi: 10.1016/s0891-5849(99)00203-8.
• Vassalle C, Pratali L, Boni C, Mercuri A, Ndreu R. An oxidative stress score as a combined measure of the pro-oxidant and anti-oxidant counterparts in patients with coronary artery disease. Clin Biochem. 2008 Oct;41(14-15):1162-7. doi: 10.1016/j.clinbiochem.2008.07.005. Epub 2008 Jul 26.
• Fallo F, Della Mea P, Sonino N, Bertello C, Ermani M, Vettor R, Veglio F, Mulatero P. Adiponectin and insulin sensitivity in primary aldosteronism. Am J Hypertens. 2007 Aug;20(8):855-61. doi: 10.1016/j.amjhyper.2007.03.012.
• Iacobellis G, Petramala L, Cotesta D, Pergolini M, Zinnamosca L, Cianci R, De Toma G, Sciomer S, Letizia C. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab. 2010 May;95(5):2391-8. doi: 10.1210/jc.2009-2204. Epub 2010 Mar 1.
• Giacchetti G, Sechi LA, Rilli S, Carey RM. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab. 2005 Apr;16(3):120-6. doi: 10.1016/j.tem.2005.02.003.
• Lucatello B, Benso A, Tabaro I, Capello E, Caprino MP, Marafetti L, Rossato D, Oleandri SE, Ghigo E, Maccario M. Long-term re-evaluation of primary aldosteronism after medical treatment reveals high proportion of normal mineralocorticoid secretion. Eur J Endocrinol. 2013 Mar 15;168(4):525-32. doi: 10.1530/EJE-12-0912. Print 2013 Apr.
• Rossi GP, Maiolino G, Flego A, Belfiore A, Bernini G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Muiesan ML, Mannelli M, Negro A, Palumbo G, Parenti G, Rossi E, Mantero F; PAPY Study Investigators. Adrenalectomy Lowers Incident Atrial Fibrillation in Primary Aldosteronism Patients at Long Term. Hypertension. 2018 Apr;71(4):585-591. doi: 10.1161/HYPERTENSIONAHA.117.10596. Epub 2018 Feb 26.
• Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008 Jun 7;371(9628):1921-6. doi: 10.1016/S0140-6736(08)60834-X. Erratum In: Lancet. 2008 Dec 13;372(9655):2022.
• Marzano L, Colussi G, Sechi LA, Catena C. Adrenalectomy is comparable with medical treatment for reduction of left ventricular mass in primary aldosteronism: meta-analysis of long-term studies. Am J Hypertens. 2015 Mar;28(3):312-8. doi: 10.1093/ajh/hpu154. Epub 2014 Oct 21.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2011
• Primary Completion (Actual): September 30, 2020
• Study Completion (Anticipated): October 31, 2025

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 26, 2019
• First Posted (Actual): December 30, 2019

Study Record Updates

• Last Update Posted (Actual): November 3, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Oxidative Stress; Blood Pressure; Resistant Hypertension; Primary Aldosteronism; Renin-Angiotensin System; Cardiometabolic Risk; Early Atherosclerotic Damage
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Endocrine System Diseases; Arrhythmias, Cardiac; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Hypertension; Atrial Fibrillation; Hyperaldosteronism
• Other Study ID Numbers: The PrePARe Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No