# Digoxin Calculator

## Digoxin dosing tool for heart failure and atrial fibrillation

### Patient Parameters

 Age years Height in cm Weight kg lbs Gender Male Female Creatinine mg/dL µmol/L Indication CHF Afib Both

### Digoxin Parameters

 Dosage form Tablet Injection (IV) Elixir Target level
RESULTS

#### Dosing

0.0625 mg once daily
(0.125 mg every other day)

#### Predicted trough

0.7 ng/mL
(goal 0.5 to 1 ng/mL)

#### Other dosing strategies:

Dose Trough
0.0625 mg daily 0.7 ng/mL
0.125 mg daily 0.99 ng/mL
0.250 mg daily 1.27 ng/mL
Ideal Body Weight (Devine 1974)
$$\\IdealBW = 45.5 + 2.3*(height\;over\;60\;inches)\\ IdealBW = 45.5 + 2.3*(66-60) = 59.3\;kg \\ Weight\;for\;CrCl = IdealBW + 0.4*(ActualBW-IdealBW)$$
Creatinine Clearance (Cockcroft-Gault 1976)
$$\\ CrCl =\frac{(140-Age)*(Weight)}{72*SCr}*0.85\;(female)\\ = \frac{(140-81\;yrs)*69.18\;kg}{72*1.2\;mg/dL}*0.85\;(female) =40\;mL/min$$
Digoxin dose and predicted level (Bauman 2006)
$$\\ Dose = -2.247 + (0.0244 * CrCl) + (0.0383 * IdealBW) = 1\\ (1 = 0.0625\;mg/day,\;2 = 0.125\;mg/day,\;3 = 0.250\;mg/day)$$
$$Level = 1.345 + (0.287 * CodedDose) - (0.007 * CrCl) - (0.011 * IdealBW)\\ = 1.345 + (0.287 * 1) - (0.007 * CrCl) - (0.011 * IdealBW) = 0.7\;ng/mL$$

This calculator uses two different equations depending on the patient's comorbidities:

• Heart failure (without arrhythmias): Historically, the Jelliffe1 and Koup and Jusko2,3 methods have been commonly used; however, these equations target a higher digoxin concentration that may be inappropriate on the basis on the data from the Digitalis Investigation Group (DIG) post-hoc analysis.4 For this reason, this calculator is based on a newer equation and nomogram published by Bauman and DiDomenico,5 which targets a more appropriate digoxin concentration of 0.7 ng/mL and has been shown to be more accurate than other estimation methods in a modern heart failure population.2,3
• Atrial fibrillation: Historically, the Jelliffe1 equation has been used, but is less accurate in patients with impaired renal function. Therefore, this calculator uses the methods described by Koup and Jusko.2,3
• Heart failure with atrial fibrillation: There is insufficient data regarding the appropriate digoxin concentration for patients with heart failure and concomitant atrial fibrillation. The DIG trial6 specifically excluded patients with atrial fibrillation, which limits the external validity of the DIG trial findings to this patient population. For this reason, this calculator uses the Koup and Jusko method2,3 for these patients.

Of note, these equations utilize an ideal body weight equation7 to estimate lean body weight, which has been shown to be most predictive of appropriate dosing, even in morbidly obese patients.8

#### Bauman-DiDomenico Nomogram

As mentioned above, this calculator uses the Bauman-DiDomenico nomogram for dosing heart failure patients (without arrhythmias). This nomogram, shown below, is specifically intended for a more appropriate digoxin concentration of 0.7 ng/mL and has been shown to be more accurate than the traditional Jellife or Koup and Jusko methods.5

#### This calculator is not appropriate for the following patient populations:

• Significant drug interactions (eg, amiodarone, quinidine, verapamil, or macrolide antibiotics)
• End-stage renal disease on hemodialysis
• Acute renal failure or unstable renal function

#### The following bioavailabilities (F) are used for calculation:

• Tablet = 0.75
• Intravenous = 1
• Elixir = 0.8

### Clinical Evidence for Digoxin in Heart Failure

Digitalis glycosides, like digoxin, have been used for more than 200 years to treat heart failure, but until recently, have had little clinical evidence to support their use in heart failure. In 1993, the PROVED9 and RADIANCE10 trials were published, which showed improvement in surrogate endpoints for heart failure. Interestingly, these trials showed that there may not be a difference in clinical efficacy between lower digoxin concentrations (eg, less than 0.9 ng/mL) and higher concentrations.11

In 1997, the Digitalis Investigation Group (DIG) trial was published,6 which showed no improvement in mortality among patients with systolic heart failure (EF ≤ 45%) and normal sinus rhythm; however, the trial did show a decrease of 6.2% in overall hospitalizations. At the time of the trial, target digoxin concentrations were 0.5 to 2 ng/mL, which was primarily based on the drug’s toxicity rather than its efficacy.12

Following the publication of the DIG trial, a post-hoc analysis was published in 2003 examining the association of digoxin concentrations on the endpoints in the DIG trial.4 This analysis found that patients with a low digoxin concentration (0.5 to 0.8 ng/mL) showed a 6.3% reduction in mortality, patients with an intermediate concentration (0.9 to 1.1 ng/mL) showed no difference in mortality, and patients with a high concentration (> 1.2 ng/mL) showed an 11.8% increase in mortality. Although these findings are post-hoc and retrospective, it has led to a recommendation for lower goal digoxin concentrations. Additional post-hoc analyses of the DIG trial have found similar findings.13

The clinical evidence support the theory that digoxin exerts a beneficial effect in heart failure via neurohormonal modulation at lower serum concentrations; however, it may exert a harmful effect via inotropic stimulation at higher serum concentrations. Based on these findings, the most recent ACC/AHA full guidelines recommend a digoxin concentration of 0.5 to 1 ng/mL.14 Similarly, the HFSA 2010 guidelines suggest a concentration < 1 ng/mL (generally 0.7 to 0.9 ng/mL).15

Note that in clinical practice, serum digoxin concentrations should be drawn at least 6 hours following oral digoxin administration to allow for drug distribution.5 Furthermore, a steady-state concentration requires at least 1 week of consistent daily dosing in patients with normal renal function, or at least 1 month of consistent daily dosing in patients with reduced renal function (eg, creatinine clearance less than 90 mL/min).

1. Jelliffe RW. An improved method of digoxin therapy. Ann Intern Med. 1968;69(4):703-17. PMID 5682245.
2. Koup JR, Jusko WJ, Elwood CM, et al. Digoxin pharmacokinetics: role of renal failure in dosage regimen design. Clin Pharmacol Ther. 1975;18(1):9-21. PMID 1149366.
3. Jusko WJ, Szefler SJ, Goldfarb AL. Pharmacokinetic design of digoxin dosage regimens in relation to renal function. J Clin Pharmacol. 1974;14(10):525-35. PMID 4430731.
4. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871-8. PMID 12588271.
5. Bauman JL, DiDomenico RJ, Viana M, et al. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med. 2006;166(22):2539-45. PMID 17159022.
6. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-33. PMID 9036306.
7. Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–655.
8. Abernethy DR, Greenblatt DJ, Smith TW. Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J. 1981;102(4):740-4. PMID 7282520.
9. Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol. 1993;22(4):955-62. PMID 8409069.
10. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med. 1993;329(1):1-7. PMID 8505940.
11. Adams KF Jr, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol. 2002;39(6):946-53. PMID 11897434.
12. Terra SG, Washam JB, Dunham GD, et al. Therapeutic range of digoxin's efficacy in heart failure: what is the evidence? Pharmacotherapy. 1999;19(10):1123-6. PMID 10512061.
13. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006;27(2):178-86. PMID 16339157.
14. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation. 2005;112(12):e154-235. PMID 16160202.
15. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e1-194. PMID 20610207.