Screening for Primary Aldosteronism in a Population of Patients With Hypertension
Condition: Primary Aldosteronism; Hypertension; Hypertension Secondary
MeSH terms: Hypertension; Hyperaldosteronism
Study type: Observational

Summary: 
      Primary aldosteronism (PA) is an under-diagnosed cause of arterial hypertension.
      Cardiovascular morbidity and mortality in hypertension rises significantly for patients who
      have aldosterone overproduction when compared with those with primary hypertension and the
      same level of blod pressure elevation. The classical signs of PA such as severe hypertension
      and hypokalemia may be absent, why screening in defined risk groups has been recommended.
      Screening has not been systematically implemented in Sweden, probably due to expensive, time
      and effort-consuming clinical routine protocols and low awareness of the problem among
      clinicians. The prevalence of PA in patients with hypertension in Sweden has not been studied
      adequately, and few studies from Northern Europe have addressed the problem.

      The primary objective is to investigate prevalence of PA among patients with hypertension in
      primary care and to implement and assess optimal treatment. Discovered cases of PA will go
      through routine clinical work-up in order to distinguish the subtype of PA, which includes
      computed tomography of adrenals and adrenal vein sampling (AVS) in those willing and fit for
      surgical treatment. Treatment will be then chosen depending on the PA subtype. Those with
      unilateral disease who are willing and fit for surgery will be offered unilateral minimally
      invasive adrenalectomy. Patients who oppose or have contraindications to operative treatment,
      as well as patients with bilateral disease will be offered medical treatment with
      mineralocorticoid receptor antagonists (MRA).

      Study participants will be then followed up one year after surgery or initiation of specific
      medical treatment. Please se outcome measures for relevant description of those.

      Blood samples will be collected from patients with confirmed PA to be stored in a biobank for
      potential future genetical and biochemical studies. A subgroup of patients with PA will
      undergo adrenal-specific positron-emission tomography to assess the possibility to
      un-invasively diagnose and subtype PA.
    

Detailed description: 
      Primary care hypertensive patients corresponding to eligibility criteria will be contacted by
      letter (including informed consent form) and thus invited to take part in the present study.
      On the one hand, the letter will be sent to a group of hypertensive patients who could be
      identified from the hypertension diagnosis based search through the database belonging to the
      computerized patient journal system. On the other hand, the letter will be offered to
      consecutive hypertension patients who contact their primary care facility for whatever
      reason. The first 1200 patients who have given informed consent to participation are going to
      be enrolled in the study.

      The study will be conducted mostly in Karlstad, a town in central Sweden with population of
      about 89000 people. Some of approximately 4000 hypertensive patients enlisted at one of the
      major primary care facilities in town, Gripen Outpatient Clinic, will be contacted in the
      above manner. Gripen serves totally about 21000 outpatients. If needed for enrollment
      purposes, one other of the regions major outpatient clinics will be involved. Aldosterone -
      Renin Ratio (ARR), intravenous sodium chloride (i.v. NaCl) suppression test and adrenal
      computed tomography (CT) will de done at Karlstad Central Hospital - at Surgical,
      Endocrinological and X-ray Departments, respectively. AVS is planned to be carried out at an
      X-ray laboratory at Uppsala University Hospital. Adrenalectomies will be performed at
      Surgical departments in both Uppsala and Karlstad.

      After a two week run-in period with liberal salt intake and abstinence form licorice and
      chewing tobacco, blood samples will be taken from study participants. Sampling will be
      performed at 8-10 a.m., ideally 2 hrs after awakening and after 5-15 min of seated rest.

      Plasma aldosterone, plasma renin (Direct Renin Concentration, DRC), serum sodium, potassium
      and creatinine are going to be analysed. Aldosterone-Renin Ratio (ARR) > = 50 pmol/mU and
      plasma aldosterone > = 170 pmol/l are the criteria that will prompt further work-up upon
      suspicion of PA. Patients with other test results will be considered to not have PA - if they
      are normokalemic and not using mineralocorticoid receptor antagonists (MRA).

      Patients using MRA will be offered optimization and retest. MRA will be then discontinued for
      at least 6 weeks and substituted if needed with alfa- or calcium blockers. Hypokalemic
      patients with test results not prompting suspicion of PA will also be optimized with
      potassium supplementation until normokalemia is sustained before retesting.

      Those with suspicion-raising ARR and aldosterone will go further in evaluation unrelated to
      potassium level, but will need to correct any hypokalemia prior to i.v. NaCl suppression
      test. Patients with suspicion of PA who have uncontrolled hypertension (with systolic blood
      pressure > 180 or diastolic pressure > 110 mm Hg) will need more efficient treatment before
      proceeding to confirmation work-up. Patients with chronic heart failure NYHA (New York Heart
      Association) stage > 2 are going to be excluded from i.v. NaCl suppression testing.

      Possibility of PA in patients excluded from the study prior to confirmation work-up can be
      assessed by the criteria that may be present at the time of ARR-evaluation. Diagnosis of PA
      can be stated if initial hypokalemia, plasma renin below detection limit and plasma
      aldosterone above 550 pmol/l are encountered.

      Patients with suspected PA will be offered intravenous sodium chloride (NaCl) suppression
      test to confirm or exclude the diagnosis.The criteria used here correspond to the criteria
      recommended by the last edition of An Endocrine Society Clinical Practice Guideline for
      management of primary aldosteronism (2016).

      Intravenous sodium chloride suppression test involves intravenous administration of 2 liters
      of NaCl 0,9% solution given over 4 hours under medical observation. Post-test plasma
      aldosterone > 280 pmol/l confirms PA, aldosterone < 140 pmol/l excludes PA in normokalemic
      subjects. According to protocol amendment from February 2, 2018, patients with aldosterone
      within 140 - 280 pmol/l are going to be offered optimization with discontinuation of eventual
      potassium wasting diuretics, Amiloride and all other antihypertensive medication which can
      influence the screening test for minimum of 4 weeks besides other measures above mentioned as
      optimization before ARR - if those had not been effectively implemented before. After this
      optimization period the i.v. NaCl suppression test will be repeated. If aldosterone after
      this second NaCl suppression test is < 190 pmol/l, those patients will be considered free of
      PA and excluded form further analysis. Patients with aldosterone > = 190 pmol/l will be
      considered to have PA.

      The patients where PA has been confirmed will be evaluated onwards as previously described.

      Patients with bilateral disease will be offered medical treatment with MRA. Patients with
      unilateral disease (if fit and willing) will be recommended minimally invasive surgical
      treatment.

      Treatment results are going to be followed up after one year, as detailed in the outcome
      measures.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        An unselected population of primary care patients with hypertension
      
Biospecimen description: 
      Blood samples from patients with documented primary aldosteronism are going to be (with the
      patients informed consent) obtained to be stored in Uppsala Biobank for future scientific
      purposes.
    
Keywords: primary aldosteronism; hypertension; screening; secondary hypertension