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Letter in response to “Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)”

We read with interest the study “Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)” by Chan et al.[1] The study provides further insight into the clinical course of patients with suspected chronic digoxin overdose treated with anti-digoxin Fab. A strength of the study was its emphasis that patients chronically taking digoxin are sick with a high incidence of comorbidities and are on multiple medications that affect their hemodynamic status. This fact fuels one of our concerns that the use of hyperkalemia and renal failure to define digoxin toxicity is problematic. These patients have many reasons for their hyperkalemia, including chronic kidney disease and medications such as spironolactone. While it is known that acute kidney injury or chronic disease can precipitate digoxin toxicity due to impaired elimination, digoxin is not intrinsically renal toxic. The majority of these patients also receive drugs that independently cause bradycardia, such as beta blockers. Thus, assessing the efficacy of anti-digoxin Fab in chronic digoxin overdose is complicated by the authors’ nonspecific definition of toxicity. With bradycardia and hyperkalemia possibly being due to medication effect or other etiologies, using these criteria to define the patient as toxic may be misleading. The lack of response to Fab may be due to the fact that these patients are not digoxin toxic at all. Another concern is the potential use of predistribution digoxin concentrations to define chronic overdose. It is recommended to obtain a serum concentration at least 6–8 h after the last dose.[2] The failure to note the time of last ingestion may have led to the erroneous inclusion of patients with therapeutic concentrations whose serum samples were collected prior to tissue redistribution. In addition, most patients who received anti-digoxin Fab in this study achieved undetectable serum concentrations of free digoxin. We dispute the assertion that free serum digoxin reflects lack of clinical toxicity in this setting. Although digoxin is found in the serum, its primary sites of tissue toxicity are the comparatively vast cardiac and skeletal muscle compartments. As such, free serum digoxin should be treated as a marker – not the cause – of clinical toxicity and any anti-digoxin Fab dosing strategy aimed solely at reducing the free serum concentration risks patient harm by under-dosing the antidote. Despite these issues, the study identified some patients with true chronic digoxin overdose. Gastrointestinal (GI) symptoms figure prominently in digoxin toxicity and we believe that patients whose GI complaints disappeared after antidotal therapy likely had true disease.[3] Additionally, some patients appeared to have dramatic improvements in heart rate following Fab therapy. Analyzing the clinical and laboratory outcomes in this subgroup may provide a more accurate estimate of antidotal efficacy.