Q&A column

Editor: Frederick L. Kiechle, MD, PhD

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Q. Some recent clinical guidelines recommend lower therapeutic and toxic limits for digoxin than those provided in assay package inserts. What therapeutic ranges and toxic thresholds should laboratories use?

A.September 2023—The CAP General Chemistry and Therapeutic Drug Monitoring Survey program includes therapeutic drugs that have been in use for decades and for which numerous commercial assays are available. The serum/plasma concentrations of some drugs, such as acetaminophen, salicylate, and vancomycin, are frequently measured to assess for toxicity or as part of therapeutic drug monitoring, while other drugs, such as digoxin, are less frequently prescribed today and, therefore, less frequently assessed.

Once a mainstay for treating atrial fibrillation and heart failure, digoxin has largely been supplanted by newer medications. Because of its infrequent clinical use, health care providers and clinical laboratories may become less familiar with therapeutic drug monitoring of digoxin. However, it retains limited indications despite being widely recognized as a potentially toxic compound. More than 3,000 participants in the Survey program report digoxin measurements, on par with the number who report acetaminophen, salicylate, and vancomycin measurements.

While early studies suggested digoxin concentrations up to 2.0–2.5 ng/mL (2.6–3.2 nmol/L) were tolerable, recognition of toxicity risk at lower concentrations has led to support for lowering the upper therapeutic limit to 0.9–1.2 ng/mL (1.2–1.5 nmol/L).¹ Recent large trials and clinical guidelines also advocate lowering digoxin therapeutic ranges. These include the ARISTOTLE trial in atrial fibrillation² and the 2022 heart failure guidelines from the American Heart Association, American College of Cardiology, and Heart Failure Society of America.³

Despite concerns about risks for toxicity, recent studies support decreasing (e.g. to 0.5 ng/mL [0.6 nmol/L]) or eliminating (e.g. therapeutic range <1.0 ng/mL [<1.3 nmol/L]) the lower limit of the therapeutic range. In contrast, previous recommendations were often ≥0.8 ng/mL (≥1.0 nmol/L). Inappropriate lower limits could lead providers who are unfamiliar with digoxin management to raise doses to address perceived subtherapeutic concentrations.

Unfortunately, guidelines and clinical trials rarely address the assays used to measure digoxin or mention such issues as lack of assay standardization, evolution of methodologies, and variable influence of interfering substances.⁴ A 2013 survey of 60 laboratories found that most had upper therapeutic limits set between 2.0 and 2.5 ng/mL (2.6 and 3.2 nmol/L), reflecting older recommendations.¹ As there is little incentive for assay manufacturers to update product information, digoxin therapeutic ranges given in package inserts might not be based on recent studies or guidelines.

All laboratories performing digoxin testing are encouraged to evaluate their test performance and patient demographics, in collaboration with cardiology and other relevant clinical practices, to determine the appropriate therapeutic range for their unique population.

1. Hauptman PJ, McCann P, Ramirez Romero JM, Mayo M. Reference laboratory values for digoxin following publication of Digitalis Investigation Group (DIG) trial data. JAMA Intern Med. 2013;173(16):1552–1554.
2. Lopes RD, Rordorf R, De Ferrari GM, et al; ARISTOTLE Committees and Investigators. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol. 2018;71(10):1063–1074.
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263–e421.
4. Dasgupta A. Significant improvement in digoxin immunoassays over four decades: newer assays are less affected by interferences. Ther Drug Monit. 2023;45(1):26–34.

Christine Snozek, PhD, D(ABCC)
Codirector, Clinical Chemistry and Support Services
Director, Point of Care and Central Processing
Mayo Clinic Arizona
Phoenix, Ariz.
Member, CAP Toxicology Committee

Matthew David Krasowski, MD, PhD
Clinical Professor of Pathology
University of Iowa Hospitals and Clinics
Iowa City, Iowa
Chair, CAP Toxicology Committee