Digoxin: Does the dose fit your patient?

Calculation of estimated creatinine clearance (mL/minute):

MEN: CrCl mL/minute = (140 - age) × weight (kg) (× 0.85 for WOMEN)
Serum creatinine (umol/L) × 0.81

 

Since 1997, more than 1.2 million digoxin prescriptions have been dispensed to over 112000 patients according to BC Pharmacare data. Overall, the 0.25 mg strength accounts for 39.6% of prescriptions. While not a first-line agent, digoxin does have a role in the treatment of chronic heart failure. Digoxin is used in patients with NYHA Class II–IV heart failure who have not responded to ACE inhibitors or beta-blockers, as well as in patients with atrial fibrillation to help control ventricular response rate.[1,2] The 2001 Canadian Cardiovascular Society Consensus guidelines advise the usual maintenance dose in adults is 0.125 mg to 0.25 mg daily.[1] Recent information indicates that levels above 1.3 nmol/L (1 ng/mL) do not improve effectiveness in heart failure in contrast to the usually cited range of 0.6 nmol/L to 2.6 nmol/L (0.5 nmol/L to 2 ng/mL).[3]

Doses in women should probably be lower than in men. The Digitalis Investigation Group found that use of digoxin was associated with an increased risk of death in women with heart failure.[4] The women in the study had different causes of heart failure, for example idiopathic cardiomyopathy versus ischemic cardiomyopathy, compared to the men.[4] A study in one hospital found that mean serum digoxin levels were higher in women than in men even though serum creatinine levels were lower. Women had more reported adverse effects to digoxin than men.[5]

Drug interactions are a potential concern with concurrent digoxin use. Addition of new medications to patients stabilized on digoxin can lead to toxicity causing hospitalization or death. A recent study from Ontario showed patients admitted to hospital with digoxin toxicity were 12 times more likely to have had a prescription for clarithromycin in the week prior to admission. Clarithromycin increases digoxin levels by inhibition of P-glycoprotein, which is responsible for renal clearance of digoxin.[6] Other medications that can increase serum digoxin levels include:[7]

• amiodarone (increases levels by 70% to 100%)
• some calcium channel blockers (e.g., diltiazem, verapamil)
• flecainide
• quinidine, quinine
• ketoconazole, itraconazole
• azithromycin, clarithromycin, erythromycin 
• fluoxetine, nefazodone, trazodone

Diuretics and NSAIDS may interfere with renal function and could cause toxicity.

Conclusion

To minimize toxicity, physicians should ensure that digoxin is being prescribed at the lowest effective dose and that it does not interact with concurrent medications. Levels should be done initially, then repeated if the patient is suspected of being noncompliant or is at risk of toxicity (loss of body mass, worsening renal function, or the potential for drug interactions).[1] Use of the Cockcroft Gault equation for estimation of creatinine clearance is encouraged. Doses should be adjusted if the creatinine clearance (CrCl) is decreasing. If CrCl is 10 mL/minute to 50 mL/minute, use 25% to 75% of the usual dose or give the normal dose every 36 hours. If CrCl is <10 mL/minute, use 10% to 25% of the usual dose or give the normal dose every 48 hours.[7]


References

1. Liu P, Arnold M, Belenkie I, et al. The 2001 Canadian Cardiovascular Society consensus guideline update for the management and prevention of heart failure. Can J Cardiol 2001;17(suppl E):5E-25E.PubMed Citation
2. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-1833.PubMed Abstact Full Text
3. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-878.PubMed Abstract Full Text
4. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411.PubMed Abstract Full Text
5. Hallberg P, Michaelsson K, Melhus H. Digoxin for the treatment of heart failure. [letter] N Engl J Med 2003;348:661-663.PubMed Citation
6. Juurlink DN, Mamdani M, Kopp A, et al. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652-1658.PubMed Abstract Full Text
7. Cadario BJ, Leathem AM (eds). Drug information reference. 5th ed. Vancouver, BC: The BC Drug and Poison Information Centre, 2003.

Kathy McInnes, BSc(Pharm)
Derek Daws, BSc(Pharm)
BC Drug & Poison Information Centre

Kathy McInnes, BSc(Pharm), Derek Daws, BSc(Pharm). Digoxin: Does the dose fit your patient?. BCMJ, Vol. 45, No. 7, September, 2003, Page(s) 310 - BCCDC.



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