Serum Digoxin Concentrations: Do You Know the Current Upper Limit in Heart Failure?

For more than 30 years, serumdigoxin concentrations (SDCs)have been monitored toensure safe, effective therapy.^1,2Although the therapeuticrange for SDCs is often listed as either0.8 to 2.0 ng/mL or 0.5 to 2.0ng/mL, the results of clinical trials inthe 1990s suggest an upper limit of1.0 ng/mL for treatment of heart failure.^3-11 An upper limit for the SDC of1.0 ng/mL is also recommendedfor patients who have heart failureand atrial fibrillation with rapid ventricularresponse.THE CASE FOR AREDUCED UPPER LIMITListing the upper limit of thetherapeutic range as 1.0 ng/mL onlaboratory report forms may helpavoid unnecessarily high SDCs. Alower SDC minimizes the risk ofdigoxin toxicity without sacrificingtherapeutic benefit in patients withheart failure.Some clinicians use the serumconcentration ranges listed on laboratoryreports as guidelines for treatment.This practice can lead the clinicianto order higher digoxin doses toattain the upper range limit (2.0ng/mL)--with the incorrect assumptionthat this will improve patient outcome.If the upper therapeutic limit is1.0 ng/mL, clinicians are not "invited"to increase the dose--and thus theSDC--with greater risk of digoxintoxicity. Assessment of SDC in thetreatment of atrial fibrillation withoutconcurrent heart failure, which mayrequire a higher SDC for ventricularrate control,¹² is not within the scopeof this discussion.SUPPORTIVE EVIDENCEThree major clinical trials in the1990s reconfirmed the value of digoxinin treating heart failure.^9-11 Theresults of these studies also supporta reduced upper limit for SDC in thetreatment of heart failure. The Tablelists the mean SDCs in these landmarkstudies; also included in theTable are appropriate upper limits forthe SDC suggested by the results ofthe PROMISE trial⁴ and by the HeartFailure Society of America.¹³ Sometextbooks may still list the formerlyaccepted range for SDC.¹⁴OTHER POINTERSFOR SAFE,EFFECTIVE THERAPY

• Draw samples to measure SDCpreferably during troughs, when asteady-state concentration will occur.
• Take into account factors, such asrenal function, electrolyte levels, anddrug interactions, that affect interpretationof the SDC.
• Finally, it may help to separate thetherapeutic range for SDC in heartfailure (0.5 to 1.0 ng/mL) from thehigher SDC that may be required inthe treatment of atrial fibrillation withoutconcurrent heart failure.

References:

REFERENCES:

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2.

Beller GA, Smith TW, Abelmann WH, et al. Digitalisintoxication: a prospective clinical study withserum level correlations. N Engl J Med. 1971;284:989-997.

3.

Slatton ML, Irani WN, Hall SA, et al. Does digoxinprovide additional hemodynamic and autonomicbenefit at higher doses in patients with mild to moderateheart failure and normal sinus rhythm? J AmColl Cardiol. 1997;29:1206-1213.

4.

Mancini DM, Benotti JR, Elkayam U, et al. Antiarrhythmicdrug use and high serum levels ofdigoxin are independent adverse prognostic factorsin patients with chronic heart failure (abstract). Circulation.1991;84:II-243.

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Gheorghiade M, Hall VB, Jacobsen G, et al. Effectsof increasing maintenance dose of digoxin onleft ventricular function and neurohormones in patientswith chronic heart failure treated with diureticsand angiotensin-converting enzyme inhibitors.Circulation. 1995;92:1801-1807.

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Young JB, Gheorghiade M, Packer M, et al. Arelow serum levels of digoxin effective in chronicheart failure? Evidence challenging accepted guidelinesfor a therapeutic serum level of the drug (abstract).J Am Coll Cardiol. 1993;21:378A.

8.

Adams KF, Gheorghiade M, Uretsky BF, et al.Clinical benefits of low serum digoxin concentrationsin heart failure (abstract). J Am Coll Cardiol.1999;33:185A.

9

. Packer MP, Gheorghiade M, Young JB, et al.Withdrawal of digoxin from patients with chronicheart failure treated with angiotensin-converting enzymeinhibitors. N Engl J Med. 1993;329:1-7.

10

. Uretsky BF, Young JB, Shahidi E, et al. Randomizedstudy assessing the effect of digoxin withdrawalin patients with mild to moderate chroniccongestive heart failure: results of the PROVEDtrial. J Am Coll Cardiol. 1993;22:955-962.

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The Digitalis Investigation Group. The effect ofdigoxin on mortality and morbidity in patients withheart failure. N Engl J Med. 1997;336:525-533.

12.

Goldman S, Probst P, Selzer A, et al. Inefficacyof “therapeutic” serum levels of digoxin in controllingthe ventricular rate in atrial fibrillation. Am JCardiol. 1975;35:651-655.

13.

Heart Failure Society of America. HFSA guidelinesfor management of patients with heart failurecaused by left ventricular systolic dysfunction-pharmacological approaches. Pharmacotherapy.2000;20:495-522.

14

. Sameri RM, Soberman JE, Finch CK, Self TH.Lower serum digoxin concentrations in heart failureand reassessment of laboratory report forms. Am JMed Sci. 2002;324:10-13.