MRA and ARB Treatment in Screening of Primary Aldosteronism
Condition: Primary Aldosteronism Due to Aldosterone Producing Adenoma
MeSH terms: Adenoma; Hyperaldosteronism
Study type: Observational

Summary: 
      Current guidelines recommend withdrawal of treatments that affect the aldosterone/renin ratio
      (ARR) when screening for primary aldosteronism (PA). However, abandonment of
      mineralocorti-coid-receptor antagonist (MRA) and/or blockers of the renin-angiotensin system
      can deteriorate control of blood pressure (BP) and hypokalemia. Thus, in consecutive patients
      with an unambiguous diagnosis of PA in wash-out from confounding treatments and subtyped by
      AVS, the investigators have compared within-patient the plasma aldosterone and active renin
      concentration, and the ARR values, measured at baseline, and after a one-month treatment with
      MRA alone and combined with an AT-1 receptor blocker (ARB). Patients on a regular salt intake
      have been treated with canrenone (50-100 mg orally) for 1 month, after which olmesartan (10
      or 20 mg orally) has been added for another month with up-titration of both treatments over
      the first 2 weeks to control BP and hypokalemia, however maintaining background therapy. The
      biochemical variables and the ARR have been assessed in an identical manner at baseline
      values and after each month of treatment. The investigators calculated that with a sample
      size of 40 patients the study will have a 95% power to show a clinically significant 20%
      change in the ARR at an 5% alfa-value using a two-sided paired t-test. Hence, this study will
      allow to determine if an MRA alone, or added to an ARB at doses that control BP and
      hypokalemia, affect or not the ARR, thus allow to establish if these agents can be
      administered or must be forbidden during the screening of PA.
    

Detailed description: 
      Primary aldosteronism (PA) is a common form of hypertension caused by aldosterone secretion
      inappropriate for blood pressure (BP) and volume status. It involves over 11% of the patients
      referred to specialized hypertension centres, about one fifth of those with drug-resistant
      hypertension and even a large proportion of the hypertensive patients seen in general
      practice. The only main subtype of PA that can be unambiguously diagnosed based on
      post-adrenalectomy using a "five corners" approach is aldosterone-producing adenoma (APA).

      In patients undergoing screening for PA the current guidelines recommend pharmacological
      wash-out or, more correctly, switch to antihypertensive therapy not influencing the values of
      plasma aldosterone concentration (PAC) and direct renin concentration (DRC) and therefore of
      the aldosterone/renin ratio (ARR). This therapy generally entails a long-acting calcium
      channel blocker, alone or in combination with an alpha-blocker. However, a significant
      proportion of hypertensive patients, about one third, require more complex therapies to
      maintain acceptable BP levels. In addition, a proportion, estimated at around 10% of patients
      with PA, have hypertension resistant to common antihypertensives, as shown in the PATWAY-2
      study. Noteworthy, these patients usually exibit a BP lowering response to
      mineralocorticoid-receptor antagonists (MRAs).

      MRAs act as diuretics and therefore stimulate the renin-angiotensin-aldosterone system
      (RAAS), which might confound the results of the diagnostic tests, increasing renin and
      therefore reducing the ARR. This is considered to increase the rate of false negative tests.
      Moreover, some data suggest that MRA could inhibit the synthesis of aldosterone. However,
      this remains contentious as there are no prospective studies in this regard. Therefore, the
      use of MRAs, which can effectively control BP and hypokalemia during the PA screening is
      generally discouraged, despite the lack of solid prospective studies in this regard.

      The stimulation of SRAA, if it actually occurs in a patient with PA, could be controlled, or
      prevented, by the use of an angiotensin AT-1 receptor blocker.

      Therefore, the investigators set out a prospective observational study aimed at
      investigating, with a within-patient comparison, the values of PAC, DRC, ARR, serum
      potassium, in addition to blood pressure, in patients unambigously diagnosed with PA, who
      underwent screening and subtyping in washout from confounding treatments according to the
      current guidelines, with the values produced by treatment with MRA (canrenone) given alone or
      in combination with an angiotensin AT-1 receptor blocker (olmesartan).

      Methods:

      The investigators will prospectively recruit consecutive PA patients which have been
      previously studied in washout from confounding treatments (first basal evaluation) and will
      be subtyped by adrenal vein sampling (AVS) in the Clinica dell'Ipertensione Arteriosa,
      University of Padova, Italy (second basal evaluation). Inclusion criteria: patients between
      the ages of 18 and 75, diagnosed with APA according with the guidelines, which will give
      written informed consent. The exclusion criteria comprise the refusal to participate in the
      study of the history of intolerance or allergy to canrenone or ARBs.

      Patients will be treated with canrenone 50-100 mg orally for 1 month followed by canrenone
      plus olmesartan 10 or 20 mg for another month. At the end of each month they will undergo a
      clinical and biochemical reevaluation to investigate the effects of both treatments and
      compared with the ARR values observed during washout (i.e. during the first and second basal
      evaluations).

      Study design:

      After two biochemical and clinical evaluations under baseline conditions and after
      pharmacological washout from diuretics, betablockers, ARBs or ACEI (about 4 weeks) and MRAs
      (abut 6 weeks), PA patients will be treated with canrenone 50-100 mg orally once a day. After
      one and tho weeks the dose will be doubled if necessary to control BP and serum potassium.
      After one month of such therapy they will undergo the a clinical and biochemical evaluation
      (FW1) in a manner identical to the two basal evaluations.

      After, they will continue with a combination therapy with canrenone, at the dose reached,
      plus olmesartan starting with 10 mg a day for oral administration, a dose that can be
      doubled, if necessary, to achieve normotension.

      At the end of the second month of the double therapy, patients will undergo a biochemical
      re-evaluation at the Center of Hypertension (FW2) with methods identical to those performed
      in the two baseline evaluations and after one month of canrenone.

      This protocol is commonly used in the Center of Reference - UOSD Hypertension for the optimal
      preparation of patients with PA for the eventual intervention of laparoscopic adrenalectomy.

      Primary endpoint:

      This is a prospective, within-patient, observational study aiming at comparing, in patients
      with PA, the values of PAC, DRC and ARR assessed in wash-out (or in treatment with CCBs and
      or alfa-blockers) with the values observed after 1 month treatment with canrenone 50 or 100
      mg o.d. and after another month treatment with canrenone 50 or 100 mg o.d. plus olmesartan 10
      mg or 20 mg o.d.

      Sample size calculation and statistical analysis A statistical power to detect any
      intra-patient difference of ormonal concentrations will be reached considering 40 patients.

      The analysis of the data will be performed initially globally (i.e. on the entire cohort) and
      subsequently conducted separately: in patients with APA where the diagnosis will be confirmed
      at the adrenalectomy and biochemical follow-up one month after surgery, and in patients with
      PA not lateralized where the one month follow up will be performed.

      Expected Results. The investigators expect to conclusively determine if and how MRA alone or
      combined with an ARB at doses that control BP and hypokalemia, affect plasma concentration of
      PAC and DRC and therefore the ARR.

      If the results of this study will not show a confounding effect of one or the other
      treatment, this study could open the way to perform the screening tests for PA without the
      need to suspend these treatments and therefore with the possibility of minimizing the risks
      due to the reduction of therapy antihypertensive in hypertensive patients.
    

Intervention name(s): canrenone 50-100 mg orally once a day; olmesartan 10-20 mg orally once a day
Intervention type(s): Drug; Drug
Intervention description(s): After two biochemical and clinical evaluations under baseline conditions and after pharmacological washout from diuretics, betablockers, ARBs or ACEI (about 4 weeks) and MRAs (abut 6 weeks), PA patients will be treated with canrenone 50-100 mg orally once a day. After 1 or 2 weeks the dose will be doubled if necessary to control BP and serum potassium.; After one month of treatment with canrenone the patients will undergo a clinical and biochemical evaluation (FW1) in a manner identical to the two basal evaluations. After, they will continue with a combination therapy with canrenone, at the dose reached, plus olmesartan starting with 10 mg a day for oral administration, a dose that could be doubled, if necessary, to achieve normotension.
At the end of the second month of the double therapy, patients will undergo a biochemical re-evaluation at the Center of Hypertension (FW2) with methods identical to those performed in the two baseline evaluations and after one month of canrenone.
Intervention MeSH terms: Olmesartan; Canrenone
Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Consecutive PA patients subtyped with adrenal vein sampling (AVS) at the University of
        Padova, Italy
      
Biospecimen description: 
      plasma
    
Keywords: renin; aldosterone; aldosterone to renin ratio