Research Letter |

Reference Laboratory Values for Digoxin Following Publication of Digitalis Investigation Group (DIG) Trial Data

Paul J. Hauptman, MD1,2; Patrick McCann, MD1,2; Jorge M. Ramirez Romero, MD2; Mary Mayo, PhD3
[+] Author Affiliations
1Division of Cardiology, Saint Louis University School of Medicine, St Louis, Missouri
2Department of Medicine, Saint Louis University School of Medicine, St Louis, Missouri
3Department of Pathology, Saint Louis University School of Medicine, St Louis, Missouri
JAMA Intern Med. 2013;173(16):1552-1554. doi:10.1001/jamainternmed.2013.7756.
Text Size: A A A
Published online


The translation of new findings into clinical practice is an ongoing challenge for physicians and health systems. The definition of a reference range for serum digoxin concentration (SDC) in patients with heart failure provides an example in which published data have not been incorporated into laboratory practice, which as a result may have an adverse impact on clinical care.

Specifically, in a post hoc analysis from the Digitalis Investigation Group (DIG) heart failure trial, higher mean SDCs were associated with increased mortality; the optimal therapeutic range for clinical benefit among men with a left ventricular ejection fraction of less than 45% was 0.5 to 0.8 ng/mL.1 A second analysis indicated that SDCs of 1.2 ng/mL or higher may be harmful in women.2 (To convert digoxin to nanomoles per liter, multiply by 1.281.) In light of these studies, we sought to determine the current practice of reporting SDCs in hospital-based chemical laboratory analyses.

Figures in this Article

Sign In to Access Full Content

Don't have Access?

Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more

Subscribe for full-text access to content from 1998 forward and a host of useful features

Activate your current subscription (AMA members and current subscribers)

Purchase Online Access to this article for 24 hours

First Page Preview

View Large
First page PDF preview


Place holder to copy figure label and caption
Figure 1.
Reference Ranges for Therapeutic Serum Digoxin Concentration Reported by Chemical Laboratory Analyses

To convert digoxin to nanomoles per liter, multiply by 1.281.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Mean Serum Digoxin Concentrations (SDCs) Reported by Chemical Laboratory Analyses Within Defined Ranges (A) and by Percentage of SDCs Higher Than 1.5, 2.5, and 5 ng/mL (B)

To convert digoxin to nanomoles per liter, multiply by 1.281.

Graphic Jump Location




Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment
Questioning the role of digoxin in the modern era regardless of therapeutic range
Posted on September 28, 2013
Marta Miyares, Pharm.D., BCPS (AQ Cardiology)
Jackson Memorial Hospital
Conflict of Interest: None Declared
The Research Letter1 on reference laboratory values for serum digoxin concentration (SDC) confirms that most chemistry laboratory respondents surveyed still use a reference range of 0.8 to 2.0 ng/mL. This range includes SDCs of 1.2 ng/mL and higher which correlated with increased mortality in the Digitalis Investigation Group (DIG) heart failure (HF) post hoc analysis trial.2 Although I concur with the authors’ recommendations to limit the reference laboratory value to 0.9 ng/mL, attention needs to be drawn to recent published literature associating digoxin with increased mortality3-5 at SDCs close to the upper limit value that demonstrated clinical benefit in the DIG post hoc analysis trial.5 Freeman et al. enrolled patients diagnosed with systolic HF newly initiated on digoxin and followed them for 2.5 years.5 In this study, digoxin use was associated with increased mortality in both men and women. Among patients who received digoxin, the mean SDC was 1.02 ng/mL. No statistically significant difference was noted in the SDC among those who died and those who lived. As results of this trial differ from the DIG post hoc analysis trial, the earlier reported neutral mortality effects of digoxin among those with SDCs between 0.9 to 1.1 ng/mL must be questioned in an era where the use of mortality reducing agents (ACE inhibitors, β-blockers) for HF are commonly used, potentially altering the effects of digoxin when used at or even slightly above the recommended therapeutic range of 0.5 to 0.8 ng/mL.As more studies are correlating digoxin with increased mortality, regardless of an elevated SDC, further discussion as to place in therapy in the modern era including who would benefit from the authors’ recommended reference range is warranted. Nevertheless, this recent and relevant trial further validates the recommendations of Hauptman and colleagues to limit the digoxin reference range to 0.9 ng/mL. References1. Hauptman PJ, McCann P, 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. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871- 878.3. Butler J, Anand IS, Kuskowski MA, Rector T, Carson P, Cohn JN; Val-HeFT Investigators. Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val- HeFT). Congest Heart Fail. 2010;16:191–195.4. Georgiopoulou VV, Kalogeropoulos AP, Giamouzis G, et al. Digoxin therapy does not improve outcomes in patients with advanced heart failure on contemporary medical therapy. Circ Heart Fail. 2009;2:90–97.5. Freeman JV, Yang J, Sung SH, Hlatky MA, Go AS. Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure. Circ Cardiovasc Qual Outcomes. 2013;6(5):525-533.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 1

Sign In to Access Full Content

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles