Digoxin Assays: Frequent, Substantial, and Potentially Dangerous Interference by Spironolactone, Canrenone, and Other Steroids

BACKGROUNDA case of digoxin toxicity resulted from falsely low values with the MEIA II assay for digoxin (AxSYM; Abbott). The low results were caused by negative interference from canrenone and spironolactone, the latter of which has recently been advocated for the treatment of severe heart failure. Analytical interference from spironolactone has been reported, but little information is available for this effect with newer digoxin assays.METHODSWe examined nine assays (AxSYM, IMx, TDx, Emit, Dimension, aca, TinaQuant, Elecsys, and Vitros for interference by spironolactone, canrenone, and three metabolites. Additionally, all routine digoxin measurements (AxSYM) over a period of 16.5 months (n = 3089) were monitored for interference.RESULTSSuppression of the expected values by canrenone (3125 microg/L) was observed for the AxSYM (42% of expected value), IMx (51%), and Dimension (78%) assays. A positive bias was observed for the aca (0.7 microg/L), the TDx (0.62 microg/L), and the Elecsys (>0.58 microg/L). Twenty-five of 669 routinely monitored patients had falsely low results. Nineteen of these had potentially toxic concentrations of digoxin (Emit; >2.0 microg/L), although the AxSYM assay indicated therapeutic or less severe toxic concentrations (Delta(max) = 7.1 microg/L). Except for two unresolved cases, this was attributable to spironolactone, canrenone, hydrocortisone, or prednisolone. Standard doses of spironolactone (up to 50 mg/day) in patients with heart failure displayed inhibition <11%.CONCLUSIONSThe frequency and magnitude of the false-negative results particularly compromise the use of both microparticle enzyme immunoassays. Not only may toxic concentrations remain unidentified, but intoxication could occur should dosage be increased because of falsely low results. With 11 million digoxin tests/year ordered in the US, conceivably many patients could be adversely affected.