How long should Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) be stopped before testing for aldosterone and renin activity?

Duration for Stopping ACE Inhibitors or ARBs Before Aldosterone and Renin Testing

ACE inhibitors and ARBs should be discontinued for at least 2 weeks prior to testing for aldosterone and renin activity to avoid false negative results. 1, 2

Rationale for Medication Withdrawal

• ACE inhibitors and ARBs significantly affect the renin-angiotensin-aldosterone system (RAAS), causing increased renin levels and decreased aldosterone levels, which can lead to false negative results in aldosterone-to-renin ratio (ARR) testing 1, 2
• These medications can suppress the ARR by up to 48% within 2 weeks of initiation, making them potent confounders when evaluating for primary aldosteronism 3
• While traditional guidelines recommended a 4-6 week withdrawal period, more recent evidence supports a 2-week protocol as sufficient for most patients 4

Evidence Supporting 2-Week Withdrawal Period

• A retrospective study demonstrated that a 2-week withdrawal protocol for renin-stimulating antihypertensives was sufficient to achieve renin suppression in 94% of patients undergoing adrenal vein sampling 4
• In this study, 100% of procedures were diagnostic after the 2-week withdrawal period, with successful lateralization confirmed in appropriate patients 4
• The 2017 ACC/AHA guidelines acknowledge that medications affecting the RAAS must be withdrawn before testing but do not specify an exact timeframe 1

Special Considerations

• Patients should maintain unrestricted salt intake and have serum potassium in the normal range during the testing period 1
• Hypokalemia should be corrected before testing as it can independently suppress aldosterone production and lead to false negative results 2
• In patients with severe hypertension who cannot tolerate medication withdrawal for the full recommended period, the 2-week protocol may be considered with confirmation of renin suppression (PRA < 0.5 ng/ml/hr) 4

Alternative Approaches When Complete Withdrawal Is Not Feasible

• If ACE inhibitors or ARBs cannot be safely discontinued, consider measuring the aldosterone/angiotensin II ratio (AA2R) instead of the traditional ARR 5
• The AA2R appears to remain elevated in primary aldosteronism even during ACE inhibitor therapy, potentially avoiding false negative results 5
• For patients with difficult-to-control hypertension, temporary substitution with non-interfering agents such as verapamil slow-release, hydralazine, prazosin, or doxazosin during the withdrawal period may be considered 2

Common Pitfalls to Avoid

• Beta-blockers, alpha-methyldopa, clonidine, and NSAIDs should also be discontinued as they suppress renin and may cause false positive results 2
• Diuretics (including spironolactone and eplerenone) should be withdrawn for at least 4 weeks before testing as they can significantly alter the ARR 1, 6
• Mineralocorticoid receptor antagonists can reduce ARR and lead to false negative results in up to 48% of patients with primary aldosteronism 6
• Collection timing matters - blood should be collected mid-morning from seated patients following 2-4 hours of upright posture to improve sensitivity 2