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    1 Comment for this article
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    Questioning the role of digoxin in the modern era regardless of therapeutic range
    Marta Miyares, Pharm.D., BCPS (AQ Cardiology) | Jackson Memorial Hospital
    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.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    September 9, 2013

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

    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

    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.

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