Consider β-blocker withdrawal when using the Aldosterone Renin Ratio for case detection of Primary Aldosteronism.

Aldosterone:Renin Ratio (ARR) is the recommended test for case detection of primary aldosteronism (PA)1; despite reported diagnostic sensitivities and specificities of 66-100% and 61-96% respectively2. This variability is attributed to differences in decision thresholds, laboratory assays, study population and sampling conditions2. The Endocrine Society Clinical Practice Guideline (ESCPG), on the management of PA, is comprehensive in terms of identifying a variety of factors that impact the ARR and its interpretation, rendering both false positive and false negative screens. It acknowledges the sensitivity of the ARR to changes in renin; in particular, the potential effect of minor reductions to lead to significant changes in the ARR1 and the possibility of false positive results. In this context, patients on β-blocker therapy, agents that suppress renin production by inhibiting β1-adrenergic receptors in the kidney3 are clinically challenging.

Important novel clinical questions regarding the interpretation and measurement of the ARR in the context of β-blocker therapy remained unanswered: Can the potential for false-positive ARR test results be predicted from the β-blocker dosing regimen? Can the optimum duration of β-blocker withdrawal prior to sampling be defined? Is it safe to routinely withdraw β-blocker therapy prior to sampling? A study in healthy normotensive male volunteers demonstrated that the β-blocker, atenolol has the potential to raise the ARR sufficiently to produce a false-positive screen for PA3. Mulatero et al, studying hypertensive patients following a 1-month washout of all previous therapies, found that the introduction of atenolol was associated with a significant reduction in PRA (a less marked reduction in aldosterone) with a corresponding significant increase in ARR4.

To determine the effects of various doses of β-blocker therapy on the ARR, we conducted a cross-sectional study in subjects with hypertension and type 2 diabetes5. DRC was significantly lower in subjects on medium/high dose β-blocker therapy and PRA was significantly lower in subjects on low/medium/high dose β-blocker therapy compared to controls (no β-blocker). This finding was particularly interesting as type 2 diabetes is associated with activation of the renin-angiotensin-aldosterone-system. There was no significant change in aldosterone in subjects taking β-blockers. Consequently, the ARR using DRC was significantly higher in the medium/high dose β-blocker groups and the ARR using PRA was significantly higher in the low/medium/high dose β-blocker groups compared to controls. In fact, 8-25% of subjects in the low/medium/high dose β-blocker groups had screen positive ARR results for PA using either DRC/PRA. No subject in the control group was screen positive for PA.

A prospective longitudinal study was used to evaluate the optimal duration of β-blocker withdrawal prior to ARR sampling in patients chronically treated for hypertension6. In this cohort, 31% of subjects screened positive for PA. β-blocker withdrawal normalised the ARR due to a significant increase in DRC and PRA (with no significant change in aldosterone). This occurred within 2 weeks when ARR was calculated using DRC and within 3-6 weeks when ARR was calculated using PRA. Moreover, in individuals taking β-blocker therapy solely as antihypertensive therapy, and without cardiac indication, we found that β-blockers could be safely withdrawn without adverse effect on blood pressure.

β-blocker therapy leads to a significant increase in false positive ARR test results with associated unnecessary patient anxiety and healthcare costs. Hence, we advocate β-blocker withdrawal prior to initial ARR sampling (with an appropriate wash-out period) in patients in whom it is clinically safe to do so (e.g. no arrhythmia).

T P. Griffin1, D Wall2, G A. Browne3, M C Dennedy1, 3, P M. O’Shea4

1. Department of Endocrinology, Diabetes Mellitus and Metabolism, Galway University Hospitals, Galway, Ireland.

2. School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland.

3. Discipline of Pharmacology & Therapeutics, Lambe Institute/Translational Research Facility, School of Medicine, National University of Ireland, Galway, Ireland.

4. Department of Clinical Biochemistry, Galway University Hospitals, Galway, Ireland.

Correspondence: Paula M O’Shea, Department of Clinical Biochemistry, Galway University Hospitals, Galway; E-mail paulam.oshea@hse.ie

Tel: +353-91-544000

References:

  1. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF, Jr. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016:jc20154061.
  2. Jansen PM, van den Born BJ, Frenkel WJ, de Bruijne EL, Deinum J, Kerstens MN, Smulders YM, Woittiez AJ, Wijbenga JA, Zietse R, Danser AH, van den Meiracker AH. Test characteristics of the aldosterone-to-renin ratio as a screening test for primary aldosteronism. J Hypertens. 2014;32(1):115-26.
  3. Ahmed AH, Gordon RD, Taylor P, Ward G, Pimenta E, Stowasser M. Effect of Atenolol on Aldosterone/Renin Ratio Calculated by Both Plasma Renin Activity and Direct Renin Concentration in Healthy Male Volunteers. The Journal of Clinical Endocrinology & Metabolism. 2010;95(7):3201-6.
  4. Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, Veglio F. Drug Effects on Aldosterone/Plasma Renin Activity Ratio in Primary Aldosteronism. Hypertension. 2002;40(6):897-902.
  5. Griffin TP, Browne GA, Wall D, Dennedy MC, O’Shea PM. A cross-sectional study of the effects of β-blocker therapy on the interpretation of the aldosterone/renin ratio: can dosing regimen predict effect? J Hypertens. 2016;34(2):307-15.
  6. Browne GA, Griffin TP, O’Shea PM, Dennedy MC. β-Blocker withdrawal is preferable for accurate interpretation of the aldosterone renin ratio in chronically treated hypertension. Clin Endocrinol (Oxf). 2015.