Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment

Study Overview
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Brief Summary
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This is a prospective randomized controlled trial where quality of life and the effectiveness of treatment will be evaluated in 80 patients with confirmed unilateral primary aldosteronism ,randomly assigned to be either treated surgically with unilateral adrenalectomy or to receive medical treatment with eplerenone.

Detailed Description
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Background Primary aldosteronism (PA) is caused by hypersecretion of the adrenal hormone aldosterone and is the most common cause of secondary hypertension . The estimated prevalence of PA is 5-13% in the hypertensive population. In half of the cases, PA is caused by unilateral hypersecretion of aldosterone, most commonly from an aldosterone producing adenoma. Overproduction from both adrenals is seen in the other half, usually caused by bilateral idiopathic hyperplasia. Unilateral adrenalectomy is considered to be the treatment of choice for unilateral PA and mineralocorticoid receptor antagonists (MRAs, i.e. spironolactone or eplerenone) for bilateral PA . Untreated PA is associated with a greatly increased risk for several comorbidities, especially cardiovascular diseases and renal failure, as well as death. Studies comparing surgical and medical treatment for PA are scarce. Nevertheless, a recent meta-analysis indicated that cardiovascular outcome is better in surgically than medically treated patients . In addition, quality of life seems to improve more after surgery, and the need for antihypertensive medications, and overall health care consumption,seems to be lower following surgery . However, suboptimal dosing of MRA is common in medically treated patients with PA, which makes a fair comparison between surgically treated patients difficult. To identify candidates for surgical treatment, adrenal venous sampling (AVS) is necessary to confirm unilateral disease . However, AVS is a technically demanding procedure, with a mean success rate in non-specialized centres of only 32% . This, and the fact that AVS is not widely available, suggests that a substantial number of patients with unilateral PA are never identified and thereby not considered for surgical treatment . Rationale, aim and hypotheses Given the above, medical treatment with MRA has become the de-facto standard treatment for a large number of patients with unilateral PA, despite observational studies indicating that surgical treatment is more effective in terms of improving cardiovascular outcome, quality of life and drug load, and that it is more cost-effective. In this context the investigators have designed a prospective randomized controlled trial where we aim to compare medical and surgical treatment for unilateral PA. The investigator´s main hypothesis is that surgical treatment (adrenalectomy; standard treatment) results in better QoL at one year of follow-up compared to medical treatment with eplerenone (intervention) in patients with unilateral PA. The secondary hypotheses are: Surgical treatment is more effective than medical treatment for unilateral PA regarding a) antihypertensive effect, b) improvement in cardiometabolic risk profile, and c) health care consumption (cost-efficiency). Study Design The UPA-MEST (Unilateral Primary Aldosteronism - MinEralocorticoid antagonists versusSurgical Treatment) study is an unblinded, prospective, randomized, controlled trial. Eighty patients will be randomized to be either treated surgically with unilateral adrenalectomy or to receive medical treatment with eplerenone. After 12 months of follow-up, medically treated patients will be able to either continue with medical treatment or to be operated with unilateral adrenalectomy. Participants 80 patients with confirmed unilateral PA, aged 18-70 will participate. Inclusion and randomization After unilateral PA has been confirmed, when the patients will be informed about the disease, the patients will be informed orally, and with written information about the study, and asked to participate. Randomization will be done with random permutated blocks, generated by using a freely available software (www.randomizer.org). Treatments Surgical treatment: Minimally invasive surgery is performed via the lateral transperitoneal approach or the posterior retroperitoneal approach, with or without robotic assistance, according to the surgeon's preference. Potassium substitution > 7.5 g will be reduced by 50% on postoperative day (POD) 1, and discontinued on POD 2. Potassium substitution < 7.5 g will be discontinued on POD 1. Preoperative antihypertensive medication will be titrated to a goal blood pressure of 140/90 mmHg (14) or lower. Immunohistochemical method, using monoclonal antibodies identifying the enzymes CYP11B1 and B2, will be used to differentiate between adenoma and hyperplasia. Medical treatment: The initial dose of eplerenone is 25 mg twice daily. The dose will be increased by 50 mg every fourth week until systolic blood pressure of 140 mmHg and diastolic blood pressure of 90 mmHg or lower has been reached and biochemical control (plasma renin above the middle of the reference range, i.e >  20 mIU/L) is attained and/or hyperkalemia develops. The maximal dose of eplerenone is 300 mg twice daily. During eplerenone dose titration, the doses of other antihypertensive medications will be reduced or, if possible, discontinued. Also, potassium replacement should be discontinued. In patients who develop significant hyperkalemia (>4.6 mmol/L), the first step is to discontinue ACE inhibitors and/or angiotensin II receptor blocker (ARB). In patients not receiving treatment with ACE inhibitors or ARB, the dose of eplerenone will be decreased by 25-50 mg per day. Similarly, patients on monotherapy with eplerenone who develop very high renin concentrations and/or symptomatic hypotension, the dose of eplerenone should be decreased by 25-50 mg per day. Patients who do not attain optimal blood pressure on the maximal eplerenone dose will continue with other antihypertensive medications. It is expected that creatinine will increase in some patients, reflecting diminished renal hyperfiltration that is characteristic for patients with untreated PA. In these cases, the eplerenone dose should not be automatically reduced, and should only be considered in cases with severely worsening GFR (>1.5 from the baseline value). Follow-up Total follow-up time is 24 months. For patients in the MRA arm, there will be a possibility to cross over (opt for surgery) after 12 months. The participants will be followed on at least 7 occasions throughout the study. Outcome measures Primary endpoint: The primary endpoint is the difference in improvement of QoL between surgically and medically treated patients at 12 months, measured with EQ5D (total score and the VAS scale). Secondary endpoints: The secondary endpoints are: 1) Difference in improvement of QoL at 24 months, evaluated with EQ5D, 2) Difference in improvement of QoL at 12 and 24 months, evaluated with the SF-36/RAND-36 questionnaire, 3) The proportion of patients with complete, partial, and absent success of clinical and biochemical outcomes (based on blood pressure, use of antihypertensive drugs, plasma potassium, plasma renin and plasma aldosterone 1) according to the PASO criteria (15) at 12 and 24 months, 4) cardiovascular risk profile at 12 and 24 months, 5) difference in left ventricular mass on echocardiography at 12 and 24 months, 6) difference in renal function, evaluated by measuring eGFR and urinaryalbumin excretion at 12 and 24 months, and 7) total societal cost Statistics and power calculation Difference in treatment effects between the two groups will be analysed with paired t-test and Fishers exact test, as well as regression analyses with adjustments for age, gender, duration ofhypertension, as well as blood pressure and number of antihypertensive drugs at baseline. For power calculation we used quality of life data from Velema et al. (EQ-5D) and Ahmedet al. (RAND SF-36) . With a significance level of 5% and power of 80%, inclusion of 50-54 subjects is needed (25-27 subjects in each treatment arm) to detect a difference betweensurgically and medically treated patients. Allowing for a 20% drop out rate, inclusion is set to 80 subjects (i.e. 40 in each treatment arm). To ensure external validity, a screening log will be kept at each centre. Clinical benefits Contemporary treatment guidelines advocate surgical treatment in patients with unilateral disease. However, since AVS is not always successful, and not widely available, life-long medical treatment is often preferred for patients with PA, without any attempts to find out if they are candidates for curative surgical treatment. It is therefore of great importance to investigate if medical treatment is as effective as surgery in these patients. Currently, a head to head comparison of surgical versus medical treatments for patients with unilateral PA is lacking. If it turns out that medical treatment is as efficient and safe as surgical treatment for patients with unilateral dominant disease, a large number of patients worldwide will benefit from the study. This concerns patients treated at centres where AVS is not available, patients where the AVS has not been successful as well as patients with unilateral dominant PA who are not considered candidates for surgical intervention. Thus, the study's results have a great potential to be quickly implemented in clinical practice. Ethical considerations The main ethical issue to acknowledge is that half of the patients will be randomized to receive medical treatment, i.e. they will not receive surgical treatment that is currently considered to be standard of care for unilateral PA. However, the reasons for considering the trial to be ethical are: a) Medical treatment with mineralocorticoid receptor antagonist forpatients with bilateral PA is effective and safe, b) Thorough information about the study willbe provided before participation, c) Participation is voluntary, d) After 12 months, all medically treated patients will have the option to receive surgical treatment i.e. adrenalectomy. The study was approved by the Regional Research Ethics Committee in Gothenburg, Sweden on June 3rd, 2020 (DNR 2020-02008).

Official Title
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Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment - A Randomized Controlled Trial

Conditions
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Primary Hyperaldosteronism Due to Adrenal Adenoma

Intervention / Treatment
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* Procedure: Unilateral adrenalectomy
* Drug: Medical treatment (eplerenone)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with confirmed unilateral PA Age 18-70 years Candidate for surgical treatment No contraindications for minimally invasive surgery or treatment with MRA Understands oral and written information and provides oral and written informed consent. Exclusion Criteria: Unwilling or unable to undergo surgery Unwilling to accept medical treatment for 12 months and not receiving standard treatment (surgery) Impaired renal function with eGFR <45 ml/min/1,73m2 P-cortisol >138 nmol/L following 1-mg overnight dexamethasone suppression test.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Unblinded, prospective, multi-center,randomized, controlled trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgically Treated Primary Aldosteronism<br>Standard therapy | Procedure: Unilateral adrenalectomy<br>* Minimally invasive surgery is performed via the lateral transperitoneal approach or the posterior retroperitoneal approach, with or without robotic assistance, according to the surgeon's preference.<br>* Other names: Surgery;|
| Active Comparator: Medically Treated Unilateral Primary Aldosteronism<br>Open label eplerenone treatment | Drug: Medical treatment (eplerenone)<br>* The initial dose of eplerenone is 25 mg twice daily. The dose will be increased by 50 mg every fourth week until systolic blood pressure of 140 mmHg and diastolic blood pressure of 90 mmHg or lower has been reached and biochemical control (plasma renin above the middle of the reference range, i.e >  20 mIU/L) is attained and/or hyperkalemia develops. The maximal dose of eplerenone is 300 mg twice daily.<br>* Other names: Mineralocorticoid receptor antagonists;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life (QoL) evaluated with EuroQol-5D at 12 months | Improvement in quality of life in surgically and medically treated patients 1 year after treatment of unilateral primary aldosteronism evaluated with EuroQol-5D (EQ-5D-5LTM) | 1 year | 
| Quality of Life (QoL) evaluated with RAND SF-36 at 12 months | Improvement in quality of life in surgically and medically treated patients 1 year after treatment of unilateral primary aldosteronism evaluated with RAND SF-36. | 1 year | 
| Quality of Life (QoL) evaluated with EuroQol-5D at 24 months | Improvement in quality of life 2 years after treatment of unilateral primary aldosteronism evaluated with EuroQol-5D (EQ-5D-5LTM) | 2 years | 
| Quality of Life (QoL) evaluated with RAND SF-36 at 24 months | Improvement in quality of life 2 years after treatment of unilateral primary aldosteronism evaluated with RAND SF-36. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcome based on the Primary Aldosteronism Surgical Outcome (PASO) Criteria | To evaluate treatment effects. The proportion of patients with complete, partial or absent clinical success according to the PASO criteria | 1 year | 
| Biochemical outcome based on the Primary Aldosteronism Surgical Outcome (PASO) Criteria | To evaluate treatment effects. The proportion of patients with complete, partial or absent biochemical success according to the PASO criteria. | 1 year | 
| Left ventricular mass | To evaluate treatment effects in left ventricular mass by utilizing echocardiography at 12 months | 1 year | 
| Left ventricular mass | To evaluate treatment effects in left ventricular mass by utilizing echocardiography at 24 months | 2 year | 
| Glomerular filtration rate (GFR) as a surrogate endpoint of renal function at 12 months | To evaluate changes in renal function by assessment of glomerular filtration rate (GFR) | 1 year | 
| Albuminuria as a surrogate endpoint of renal function at 24 months | To evaluate changes in renal function by assessment of albuminuria by urine samples (urinary albumin/creatinine ratio) | 1 year | 
| Total costs | An analysis of total costs for the society will be performed based on patient baseline demographics, an analysis of treatment (in- and outpatient) associated costs, sick leave and disease- and treatment-relatedincome loss to patients and significant others, as well as disease- and treatment-related costs related costs to society. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperaldosteronism, primary aldosteronism, lateralized aldosteronism, unilateral aldosteronism, eplerenone, spironolactone, randomized trial, quality of life, PASO outcomes