Towards cost-effective diagnostic management of patients with primary aldosteronism: adrenal vein sampling or CT-scan?

Primary aldosteronism (PA) is rapidly becoming a major burden for hypertension
care. Hypertension specialists increasingly recognize that PA explains up to 6%
of cases with hypertension. In PA autonomous hypersecretion of aldosterone by
one or both adrenal glands causes hypertension that is often refractory to
treatment. PA causes vascular damage that is more severe than in subjects with
equally elevated blood pressure but without PA. PA is usually caused by either
a unilateral aldosterone-producing (micro)adenoma (APA) or by bilateral adrenal
hyperplasia (BAH). Distinction between APA and BAH is critical since the former
is treated with the aim of cure by adrenalectomy (Adx), and the latter by
mineralocorticoid receptor antagonists (MRA). After successful Adx
antihypertensive medication can usually be reduced substantially or even
stopped completely. Accurate identification of APA is therefore mandatory. The
Endocrine Society 2008 guideline recommends that in all patients with PA
sampling of both adrenal veins (AVS) for aldosterone levels should be performed
in order to detect unilateral (APA) or bilateral (BAH) hypersecretion of
aldosterone. AVS is invasive, with a small risk of adrenal hemorrhage, demands
great skill, and is expensive. Hitherto, common practice in the Netherlands has
been to diagnose APA and BAH not by AVS, but by adrenal CT-scan (non-invasive,
easy and cheap), in part because few hospitals have the facilities and
expertise to perform AVS successfully. We showed in a meta-analysis that
conclusions from AVS and CT-scan differ in 40% of cases. This discordance is
not readily explained and although AVS is attractive conceptually -because it
may detect very small adenomas whose size is below the resolution limit of CT
and because it may demonstrate non-functionality of adenomas- its superior
performance in subtyping of PA has not been demonstrated in prospective
randomized studies. The guideline's advice to perform AVS in patients with PA
is therefore debatable. In addition to the uncertainty of the validity of AVS,
the financial costs for facilities and manpower to perform AVS have not been
assessed.

Here we propose to perform a prospective, randomized, multicenter study that
compares effectiveness of AVS with effectiveness of CT-scanning for the
diagnosis of PA subtype. There is no criterion standard for accuracy of the
diagnosis of PA-subtype, but we assume that if treatment is based on a more
accurate diagnosis treatment is more effective. We therefore propose
antihypertensive medication use as a primary endpoint. Indeed, if AVS
identifies APA with better accuracy than CT it is to be expected that patients
use less antihypertensive drugs during follow-up when diagnosis is based on
AVS.

Randomized, parallel, open trial in a multi-centre setting.

APA is diagnosed by asymmetric adrenal aldosterone production as found by AVS
in one group or by a visible adenoma with normal contralateral gland when
assessed by CT in the other group. BAH will be diagnosed if AVS shows symmetric
adrenal aldosterone production or if CT scanning demonstrates bilateral adrenal
enlargement/nodularity or normal adrenal glands. In each arm Adx will be done
for APA and BAH will be treated by MRA. Hypertension will be treated according
to a strict algorithm.

The protocol follows the common practice of CT-scanning in the subtyping of PA
in one group and the recently advised alternative practice of performing a
CT-scan as well as adrenal vein sampling which currently is common practice in
the UMCs St Radboud and Groningen in the other group. Therefore, the burden of
participation is comparable to usual practice, with the exception that
follow-up is stricter and quality-of-life assessments (questionnaires) are
incorporated.
The protocol bears no direct benefit to participants. The study will however be
of great help in formulating clinical guidelines that are much better founded
in evidence and may even, in case of equivalence of the two strategies, have
substantial financial implication for society.