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Digoxin

Klassificering: C

Preparat: Digoxin BioPhausia, Lanacrist®, Lanicor, Lanoxin, Lanoxin®

ATC kod: C01AA05

Substanser: digoxin

Sammanfattning

Kvinnor med hjärtsvikt har en ökad risk för mortalitet vid behandling med digoxin. Ökad serumkoncentration hos kvinnor på grund av relativt lägre njurutsöndring av digoxin har diskuterats som orsak. Njurfunktionen måste dock alltid beaktas, i synnerhet hos äldre kvinnor med låg kroppsvikt.

Det finns beskrivet en ökad fallrisk hos män som behandlats med digoxin.

Additional information

Pharmacokinetics and dosing

The renal clearance of digoxin is reported to be around 12-14% lower in women than men [1, 2]. However, the difference is not considered to be clinically important [2]. As the therapeutic window is narrow, digoxin is mainly eliminated vi the kidneys, and renal clearance generally is lower in women, therapeutic drug monitoring of digoxin and dosage adjustment may be necessary. However, a small retrospective review of medical records (32 men, 35 women) report that the pharmacokinetics of digoxin do not appear to differ by sex [3].

Effects

The mortality risk from digoxin in atrial fibrillation treatment was similar in men and women in a large clinical trial (AFFIRM, 2466 men, 1594 women) [7] and a cohort study (ATIR-CVRN, 15191 men, 12097 women) [8].

A post-hoc subgroup analysis of the Digitalis Investigation Group (DIG) trial (5281 men, 1519 women) showed that digoxin therapy compared with placebo in heart failure was associated with increased all-cause mortality in women, but not in men [4]. This result is controversial because a sub-group analysis of the SOLVD trial (1874 men, 370 women) found no sex difference in survival [5]. However, in this study digoxin was not randomly assigned and the female sample size was very small. A Spanish study of 256 men and 94 women with heart failure also failed to show any sex difference in one-year mortality [6].Explanations for the higher mortality risk in women found in the DIG-trial are unknown, but it has been suggested it was due to higher serum concentrations or an unidentified sex-specific toxicity [4]. A retrospective analysis of the DIG-trial found a beneficial effect of digoxin on morbidity but no excess mortality in women at serum concentration of 0.5-0.9 ng/ml [9]. Based on this, the American Heart Association recommends a target serum concentration of 0.5-0.9 ng/ml, regardless of patient’s sex [10]. In conclusion, the DIG trial is the only large randomized trial showing a sex difference in survival but it is also the only of the above mentioned studies in which the effects of digoxin were compared with a properly constituted placebo group [11].

Analyses of data from the ENGAGE AF-TIMI 48 trial comparing warfarin and edoxaban in atrial fibrillation, digoxin use at baseline (3771 men, 2556 women on digoxin) was independently associated with sudden cardiac death with similar risk in men and women [12].

The effect of digoxin on vasoconstriction does not differ between men and women [13].

Adverse effects

There are conflicting results from studies whether there is an association between treatment with digoxin and the risk of falling. Risk of fracture in elderly patients treated with amiodarone or digoxin was investigated in a population-based nation-wide pharmacoepidemiological case-control study (240 428 men, 258 189 women). Risk of hip and forearm fractures were significantly reduced in both men and women with current use of digoxin [14]. In a prospective study (377 men, 602 women), digoxin treatment was an independent risk factor for falls in men but not in women [15].

In a large Dutch population-based cohort-study (1 389 225 men, 1 598 355 women), women had a 1.4-fold higher risk of digoxin intoxication than men [16].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Studies from different countries have shown that women with atrial fibrillation are prescribed digoxin more frequently than men [17, 18].

Försäljning på recept

Fler kvinnor än män hämtade ut läkemedel innehållande digoxin (ATC-kod C01AA05) på recept i Sverige år 2017, totalt 21 579 kvinnor och 18 997 män. Det motsvarar 4,3 respektive 3,8 personer per tusen invånare. Andelen som hämtat ut läkemedel ökade med stigande ålder hos båda könen. I åldersgruppen yngre än 80 år var läkemedel innehållande digoxin i genomsnitt 2,1 gånger vanligare hos män medan i åldersgruppen 80 år och äldre var det i genomsnitt 1,2 gånger vanligare hos kvinnor [19].

Uppdaterat: 2019-02-26

Litteratursökningsdatum: 2019-02-11

Referenser

  1. Yukawa E, Honda T, Ohdo S, Higuchi S, Aoyama T. Population-based investigation of relative clearance of digoxin in Japanese patients by multiple trough screen analysis: an update. J Clin Pharmacol. 1997;37:92-100. PubMed
  2. LANOXIN (digoxin). DailyMed [www]. US National Library of Medicine. [updated 2018-08-31, cited 2019-02-11]. länk
  3. Lee LS, Chan LN. Evaluation of a sex-based difference in the pharmacokinetics of digoxin. Pharmacotherapy. 2006;26:44-50. PubMed
  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;347:1403-11. PubMed
  5. Domanski M, Fleg J, Bristow M, Knox S. The effect of gender on outcome in digitalis-treated heart failure patients. J Card Fail. 2005;11:83-6. PubMed
  6. Lupón J, Urrutia A, González B, Díez C, Altimir S, Albaladejo C et al. Does heart failure therapy differ according to patient sex?. Clin Cardiol. 2007;30:301-5. PubMed
  7. Whitbeck MG, Charnigo RJ, Khairy P, Ziada K, Bailey AL, Zegarra MM et al. Increased mortality among patients taking digoxin--analysis from the AFFIRM study. Eur Heart J. 2013;34:1481-8. PubMed
  8. Freeman JV, Reynolds K, Fang M, Udaltsova N, Steimle A, Pomernacki NK et al. Digoxin and risk of death in adults with atrial fibrillation: the ATRIA-CVRN study. Circ Arrhythm Electrophysiol. 2015;8(1):49-58. PubMed
  9. Adams KF, Patterson JH, Gattis WA, O'Connor CM, Lee CR, Schwartz TA 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
  10. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327. PubMed
  11. Sica DA, Wood M, Hess M. Gender and its effect in cardiovascular pharmacotherapeutics: recent considerations. Congest Heart Fail. 2005;11:163-6. PubMed
  12. Eisen A, Ruff CT, Braunwald E, Hamershock RA, Lewis BS, Hassager C et al. Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2017;6(7):1. PubMed
  13. Freedman RR, Sabharwal SC, Desai N. Sex differences in peripheral vascular adrenergic receptors. Circ Res. 1987;61:581-5. PubMed
  14. Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in patients treated with amiodarone or digoxin for cardiac arrhythmias: a nation-wide case-control study. Osteoporos Int. 2007;18:409-17. PubMed
  15. Koski K, Luukinen H, Laippala P, Kivela SL. Physiological factors and medications as predictors of injurious falls by elderly people: a prospective population-based study. Age Ageing. 1996;25:29-38. PubMed
  16. Aarnoudse AL, Dieleman JP, Stricker BH. Age- and gender-specific incidence of hospitalisation for digoxin intoxication. Drug Saf. 2007;30:431-6. PubMed
  17. Riesgo A, Sant E, Benito L, Hoyo J, Miró O, Mont L et al. Sex differences in the treatment of patients with atrial fibrillation: population-based study in a local health district. Rev Esp Cardiol. 2011;64:233-6. PubMed
  18. Shehab A, Zubaid M, Bhagavathula AS, Rashed WA, Alsheikh-Ali AA, AlMahmeed W et al. Sex differences in management and outcomes of patients with atrial fibrillation in the Middle East: Gulf survey of atrial fibrillation events (Gulf SAFE). PLoS One. 2017;12(5):e0175405. PubMed
  19. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2019-01-30.] länk

Författare: Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson