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Research Letter |

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

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.
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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.

A brief written survey (with telephone follow-up) (eSupplement) was sent to chemistry laboratory directors at hospitals listed in the top 50 for cardiovascular medicine reported by US News and World Report3 and an additional 50 from the top 100 hospitals rated by Thomson-Reuters (now Truven Health Analytics)4 in 2012. The study was approved by the Saint Louis University institutional review board, St Louis, Missouri.

A total of 60 surveys were completed and returned for analysis (a 60% response rate). Respondents were 27 laboratory directors or assistant directors, 21 supervisors, 11 technicians, and 1 laboratory medicine fellow. Five different commercial assays were used; in the year prior to the survey, 5 laboratories changed their commercial assay citing upgrades in equipment or laboratory processes. No laboratory reported a change in the SDC reference range.

Most respondents defined a therapeutic reference range as 0.8 to 2.0 ng/mL (Figure 1); 56 of 60 report SDCs of 2.0 ng/mL or greater as being within the normal range.

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

A total of 41 laboratories reported the mean SDC evaluated over a period of up to 1 year, most commonly over the prior month (18 of 41). Nearly half (19 of 41) reported mean concentrations of 1.0 ng/mL or greater (Figure 2). A subset (33 of 41) reported on the proportion of SDCs higher than various thresholds; a significant number reported levels of 1.5 ng/mL or higher (Figure 2). When asked if SDC correlated with clinical efficacy, most respondents answered “don’t know” or “no” (76%); of the sites that answered in the affirmative (24%), only 1 site used a reference range with an upper limit lower than 1.0 ng/mL, whereas 8 listed a range up to 2 ng/mL, 1 each listed 1.5 ng/mL and 1.0 ng/mL, and 2 respondents did not provide a range.

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

In an early but influential study that helped establish the therapeutic range for digoxin, Smith et al5 reported digoxin toxicity based on electrocardiographic (ECG) manifestations. In the 0.80 to 2.4 ng/mL range, patients without evidence of ECG changes were considered to have nontoxic levels. Subsequently, data from the DIG trial suggested that SDCs lower than 0.9 ng/mL are associated with therapeutic benefit and values higher than 1.2 ng/mL may be harmful.1,2 This observation has been incorporated into practice guidelines.6

Our survey demonstrates that most laboratories closely adhere to the recommendations of the original study by Smith et al.5 Although our survey is not comprehensive, we selected a sample of hospitals ranked highest in 2 independent surveys of cardiovascular care since other hospitals likely use similar assays and ranges. In addition, the self-reported SDCs were generally higher than 1.0 ng/mL. This may partially reflect a greater propensity on the part of clinicians to check SDCs when there is a clinical suspicion of toxicity. However, although digitalis toxicity can become manifest at therapeutic serum levels and toxicity remains a clinical diagnosis, clinicians may be inappropriately reassured that their current dosing is providing a therapeutic benefit at a safe level given the published reference range.7

Of note, we obtained only a cross-sectional overview of SDCs detected in hospital-based chemical laboratory analyses and have no data on whether the levels were appropriately timed relative to dose. Furthermore, most data correlating concentrations to outcomes were generated from the DIG trial in heart failure, which excluded patients with atrial fibrillation at baseline; however, the 2 conditions often coexist. There is also no empirical evidence to suggest a therapeutic benefit of digoxin in atrial fibrillation at concentrations beyond those established for heart failure.

We previously showed that despite a secular decline in the use of digoxin, admissions for toxicity have not declined in parallel.8 As such, the persistence of a broad reference range for digoxin, a drug with a well-documented narrow therapeutic window, is a cause for concern. Based on our survey findings and a clear evidence base, we recommend the adoption of a redefined reference range for digoxin by chemical laboratory analyses with an upper limit no greater than 0.9 ng/mL and a change in laboratory reporting processes.9

Corresponding Author: Paul J. Hauptman, MD, Department of Medicine, Saint Louis University Hospital, 3635 Vista Ave, St Louis, MO 63110 (hauptmpj@slu.edu).

Published Online: June 24, 2013. doi:10.1001/jamainternmed.2013.7756.

Author Contributions: All the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hauptman.

Acquisition of data: All authors.

Analysis and interpretation of data: Hauptman and McCann.

Drafting of the manuscript: Hauptman, McCann, and Ramirez Romero.

Critical revision of the manuscript for important intellectual content: Hauptman, McCann, and Mayo.

Statistical analysis: Hauptman, McCann, and Ramirez Romero.

Administrative, technical, and material support: Hauptman, McCann, and Mayo.

Study supervision: Hauptman.

Conflict of Interest Disclosures: Dr Hauptman received an honorarium for his participation in a CME event titled “Digoxin Toxicity: Awareness, Recognition, and Treatment,” sponsored by BTG International Inc (released August 21, 2012, and available at http://theheart.medscape.org/viewarticle/767832 [sign-up required]).

Correction: This article was corrected online on June 26, 2013, to add a text citation for the eSupplement.

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.
PubMed   |  Link to Article
Adams  KF  Jr, Patterson  JH, Gattis  WA,  et al.  Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol. 2005;46(3):497-504.
PubMed   |  Link to Article
Top-ranked hospitals for cardiology and heart surgery. http://health.usnews.com/best-hospitals/rankings/cardiology-and-heart-surgery. Accessed February 16, 2013.
Leading the way to excellence. http://100tophospitals.com/top-national-hospitals. Accessed February 16, 2013.
Smith  TW, Butler  VP  Jr, Haber  E.  Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. N Engl J Med. 1969;281(22):1212-1216.
PubMed   |  Link to Article
Lindenfeld  J, Albert  NM, Boehmer  JP,  et al; Heart Failure Society of America.  HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e1-e194.
PubMed   |  Link to Article
Goldberger  ZD, Goldberger  AL.  Therapeutic ranges of serum digoxin concentrations in patients with heart failure. Am J Cardiol. 2012;109(12):1818-1821.
PubMed   |  Link to Article
Hussain  Z, Swindle  J, Hauptman  PJ.  Digoxin use and digoxin toxicity in the post-DIG trial era. J Card Fail. 2006;12(5):343-346.
PubMed   |  Link to Article
Sameri  RM, Soberman  JE, Finch  CK, Self  TH.  Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms. Am J Med Sci. 2002;324(1):10-13.
PubMed   |  Link to Article

Figures

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

Tables

References

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.
PubMed   |  Link to Article
Adams  KF  Jr, Patterson  JH, Gattis  WA,  et al.  Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol. 2005;46(3):497-504.
PubMed   |  Link to Article
Top-ranked hospitals for cardiology and heart surgery. http://health.usnews.com/best-hospitals/rankings/cardiology-and-heart-surgery. Accessed February 16, 2013.
Leading the way to excellence. http://100tophospitals.com/top-national-hospitals. Accessed February 16, 2013.
Smith  TW, Butler  VP  Jr, Haber  E.  Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. N Engl J Med. 1969;281(22):1212-1216.
PubMed   |  Link to Article
Lindenfeld  J, Albert  NM, Boehmer  JP,  et al; Heart Failure Society of America.  HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e1-e194.
PubMed   |  Link to Article
Goldberger  ZD, Goldberger  AL.  Therapeutic ranges of serum digoxin concentrations in patients with heart failure. Am J Cardiol. 2012;109(12):1818-1821.
PubMed   |  Link to Article
Hussain  Z, Swindle  J, Hauptman  PJ.  Digoxin use and digoxin toxicity in the post-DIG trial era. J Card Fail. 2006;12(5):343-346.
PubMed   |  Link to Article
Sameri  RM, Soberman  JE, Finch  CK, Self  TH.  Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms. Am J Med Sci. 2002;324(1):10-13.
PubMed   |  Link to Article

Correspondence

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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.
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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.
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