Primary aldosteronism in general practice: organ damage, epidemiology and treatment

Rationale: primary aldosteronism (PA) is the most frequent form of secondary
hypertension. It is caused by autonomous secretion of aldosterone, encompassing
a group of disorders predominated by a unilateral aldosterone-producing adenoma
(APA) and bilateral adrenal hyperplasia (BAH). Diagnosis of PA is relevant for
two reasons: 1) independent of the level of blood pressure, hypertension due to
autonomous aldosterone secretion causes more cardiovascular damage than
essential hypertension; 2) PA requires specific treatment: adrenalectomy in
case of APA and mineralocorticoid receptor antagonists (MRA) in case of BAH.
Although previously presumed a rare condition (prevalence <1%), PA is now
estimated to affect 6 to 20% of the hypertensive population. Given this high
prevalence of PA, as well as the amount of cardiovascular damage and the
available specific treatment, the question is raised whether screening of PA
should be introduced in Dutch general practice. To answer this important
question, several issues with regard to PA need to be elucidated:
1) International studies report a prevalence of PA in general practice of
6-13%. Prevalence in the Dutch population is still unknown;
2) Because of underdiagnosis of PA and long delay in diagnosis of PA after
recognition of hypertension (mean eight years), data on characteristics of
early diagnosed PA are lacking. Proof of early cardiovascular damage would
strengthen the case of screening for PA and needs to be studied;
3) Consequently, the diagnostic delay has lead to lack of data on optimal
treatment in early PA. In the current guideline (NHG-guideline Cardiovascular
risk management) a regimen of antihypertensive drugs is advised, and only if
hypertension is refractory for >6 months patients are referred. It is unknown
if hypertension is resistant to therapy in the initial phase of PA. If not,
this would also argue for early biochemical screening for PA, because even if
blood pressure is controlled, the detrimental effect of aldosterone itself will
go on unopposed. It is therefore required to study the response to
antihypertensive drugs (not MRA) in these patients.

Objectives:
Part 1) To assess the prevalence of PA in general practice (part 1 of this
study);
Part 2) To describe differences of cardiorenovascular damage in newly diagnosed
hypertensive patients with versus without PA (part 2 of this study);
Part 3) To compare the difference in blood pressure reduction to hypertensive
treatment (conventionial and with mineralocorticoid receptor antagonists) in
newly diagnosed hypertensive patients with versus without PA (part 3 of this
study).
These three objectives are essential to answer the question of whether general
practitioners should screen for PA.

Study design:
Part 1) Prospective cross-sectional study;
Part 2) Descriptive cross-sectional study;
Part 3) Clincal observational study with intervention.

• ln part 1 of the study all newly diagnosed hypertensive patients will extend
their standard diagnostic blood examination with an additional blood sample to
determine the aldosterone-renin ratio (ARR), this causes no extra burden nor
risk. In order to obtain a reliable estimate of the prevalence of PA, it is
important to collect an ARR from every patient with newly diagnosed
hypertension;
• In part 2, patients with an increased ARR will be referred to our hospital
for a sodium loading test to confirm or exclude PA. A cardiac ultrasound will
be made as part of the standard diagnostic workup. Patients will be asked to
participate in additional examinations, which includes four non-invasive
vascular measurements and testing for albuminuria. This enhanced diagnostic
workup will take 90 minutes (see next bullet for examinations and their risks);
• In part 2 a sample of patients with normal ARR (matched controls) will be
invited to participate in the following non-invasive measurements, which
encompass the following risks and burden:
a. Left ventricular mass index by cardiac ultrasound: negligible risk, no pain;
b. Intima-media thickness of carotid artery by ultrasound: negligible risk, no
pain;
c. Pulse wave velocity by Sphygmocor: negligible risk, no pain;
d. Central aortic blood pressure by Sphygmocor: negligible risk, no pain;
e. Endothelial function by flow-mediated dilation of the brachial artery:
negligible risk, uncomfortable feeling in arm during examination;
f. Albuminuria by urine sample: negligible risk, no pain.
This extended diagnostic workup will take 120 minutes.
• Patients with an increased ARR may directly benefit to a large extend from
participation, because if PA is diagnosed, they will not have the usual
diagnostic delay of PA of eight years;
• Patients with normal ARR (matched controls) will benefit from participation
at an individual level. The results of the diagnostic workup can be used as
contributing factors in the assessment of their cardiovascular risk profile
(NHG-guideline *Cardiovascular risk management*);
• In part 3 all patients will be treated with the same antihypertensive
medication they would have received if they hadn*t been included, but due to
the inclusion of the study, medication will be stopped after eight weeks. After
a 'wash-out' period of four weeks, treatment with MRA will follow. This can be
justified for three reasons:
- In non-study circumstances patients with newly diagnosed PA will receive a
diagnostic workup for subtyping PA, followed by appropriate therapy
(adrenalectomy or MRA). Because of the interruption of the standard diagnostic
workup by participation in our study, direct treatment with MRA would seem more
appropriate. However, no data exists on the effect of conventional
antihypertensive treatment in the early phase of PA, nor data that suggest
harm;
- A wash-out period of four weeks is too short cause harm. In case of
complaints due to hypertension, medication will be restarted;
- Patients without PA will be exposed for four weeks to possible adverse
effects of spironolactone (especially reversible gynaecomastia and libido loss
in men). In case of adverse effects spironolactone will be stopped and replaced
by equipotent dose of eplerenone.