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Clinical Use of Digitalis: A State of the Art Review

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Abstract

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium–potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

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References

  1. Packer M. Why is the use of digitalis withering? Another reason that we need medical heart failure specialists. Eur J Heart Fail. 2017. https://doi.org/10.1002/ejhf.1043.

    Article  PubMed  Google Scholar 

  2. Bessen HA. Therapeutic and toxic effects of digitalis: William Withering, 1785. J Emerg Med. 1986;4(3):243–8.

    CAS  PubMed  Google Scholar 

  3. Kinne-Saffran E, Kinne RK. Herbal diuretics revisited: from “wise women” to William Withering. Am J Nephrol. 2002;22(2–3):112–8.

    PubMed  Google Scholar 

  4. Groves MJ, Bisset NG. A note on the use of topical digitalis prior to William Withering. J Ethnopharmacol. 1991;35(2):99–103.

    CAS  PubMed  Google Scholar 

  5. Davis RC, Hobbs FD, Lip GY. ABC of heart failure. History and epidemiology. BMJ. 2000;320(7226):39–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pagliaro L, Colli A, Bobbio M. Individual response to treatment: from Withering to contemporary medicine. Recenti Prog Med. 2015;106(7):308–15.

    PubMed  Google Scholar 

  7. Buchtel L, Ventura HO. Lunar society and the discovery of digitalis. J La State Med Soc. 2006;158(1):26–30.

    PubMed  Google Scholar 

  8. Breckenridge A. William Withering’s legacy—for the good of the patient. Clin Med (Lond). 2006;6(4):393–7.

    PubMed  Google Scholar 

  9. Gruener A. Vincent van Gogh’s yellow vision. Br J Gen Pract. 2013;63(612):370–1.

    PubMed  PubMed Central  Google Scholar 

  10. Lee TC. Van, Gogh’s vision. Digitalis intoxication? JAMA. 1981;245(7):727–9.

    CAS  PubMed  Google Scholar 

  11. Wolf P. Creativity and chronic disease. Vincent van Gogh (1853–1890). West J Med. 2001;175(5):348.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Patel S. Plant-derived cardiac glycosides: role in heart ailments and cancer management. Biomed Pharmacother. 2016;84:1036–41.

    CAS  PubMed  Google Scholar 

  13. Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99(9):1265–70.

    CAS  PubMed  Google Scholar 

  14. Digitalis and the cardiac glycosides. Br Med J. 1969;2(5659):744–746.

  15. Digitalis Investigation G. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–33.

    Google Scholar 

  16. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114(5):397–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gjesdal K, Feyzi J, Olsson SB. Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data. Heart. 2008;94(2):191–6.

    CAS  PubMed  Google Scholar 

  18. Chekman IS. Pharmacotherapy of patients with chronic heart failure. Analysis of multicenter international studies. Lik Sprava. 2008;1–2:60–6.

    Google Scholar 

  19. Bourge RC, Fleg JL, Fonarow GC, Cleland JG, McMurray JJ, van Veldhuisen DJ, et al. Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure. Am J Med. 2013;126(8):701–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Turakhia MP, Santangeli P, Winkelmayer WC, Xu X, Ullal AJ, Than CT, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol. 2014;64(7):660–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ahmed A, Bourge RC, Fonarow GC, Patel K, Morgan CJ, Fleg JL, et al. Digoxin use and lower 30-day all-cause readmission for Medicare beneficiaries hospitalized for heart failure. Am J Med. 2014;127(1):61–70.

    CAS  PubMed  Google Scholar 

  22. Metawee M, Charnigo R, Morales G, Darrat Y, Sorrell V, Di Biase L, et al. Digoxin and short term mortality after acute STEMI: results from the MAGIC trial. Int J Cardiol. 2016;218:176–80.

    PubMed  Google Scholar 

  23. Kotecha D, Calvert M, Deeks JJ, Griffith M, Kirchhof P, Lip GY, et al. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial. BMJ Open. 2017;7(7):e015099.

    PubMed  PubMed Central  Google Scholar 

  24. Lopes RD, Rordorf R, De Ferrari GM, Leonardi S, Thomas L, Wojdyla DM, et al. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol. 2018;71(10):1063–74.

    CAS  PubMed  Google Scholar 

  25. Jaeschke R, Oxman AD, Guyatt GH. To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis. Am J Med. 1990;88(3):279–86.

    CAS  PubMed  Google Scholar 

  26. Ried LD, Horn JR, McKenna DA. Therapeutic drug monitoring reduces toxic drug reactions: a meta-analysis. Ther Drug Monit. 1990;12(1):72–8.

    CAS  PubMed  Google Scholar 

  27. Lip GY, Laroche C, Dan GA, Santini M, Kalarus Z, Rasmussen LH, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace. 2014;16(3):308–19.

    PubMed  Google Scholar 

  28. Allen LA, Fonarow GC, Simon DN, Thomas LE, Marzec LN, Pokorney SD, et al. Digoxin use and subsequent outcomes among patients in a contemporary atrial fibrillation cohort. J Am Coll Cardiol. 2015;65(25):2691–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang ZQ, Zhang R, Chen MT, Wang QS, Zhang Y, Huang XH, et al. Digoxin is associated with increased all-cause mortality in patients with atrial fibrillation regardless of concomitant heart failure: a meta-analysis. J Cardiovasc Pharmacol. 2015;66(3):270–5.

    CAS  PubMed  Google Scholar 

  30. Ouyang AJ, Lv YN, Zhong HL, Wen JH, Wei XH, Peng HW, et al. Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation. Am J Cardiol. 2015;115(7):901–6.

    CAS  PubMed  Google Scholar 

  31. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J. 2015;36(28):1831–8.

    CAS  PubMed  Google Scholar 

  32. Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015;351:h4451.

    PubMed  PubMed Central  Google Scholar 

  33. Virgadamo S, Charnigo R, Darrat Y, Morales G, Elayi CS. Digoxin: a systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction. World J Cardiol. 2015;7(11):808–16.

    PubMed  PubMed Central  Google Scholar 

  34. Qureshi W, O’Neal WT, Soliman EZ, Al-Mallah MH. Systematic review and meta-analysis of mortality and digoxin use in atrial fibrillation. Cardiol J. 2016;23(3):333–43.

    PubMed  Google Scholar 

  35. Thomsen MM, Lewinter C, Kober L. Varying effects of recommended treatments for heart failure with reduced ejection fraction: meta-analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines. ESC Heart Fail. 2016;3(4):235–44.

    PubMed  PubMed Central  Google Scholar 

  36. Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm. 2017;39(1):16–25.

    PubMed  Google Scholar 

  37. Sethi NJ, Safi S, Feinberg J, Nielsen EE, Gluud C, Jakobsen JC. Digoxin versus placebo, no intervention, or other medical interventions for atrial fibrillation and atrial flutter: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis. Syst Rev. 2017;6(1):71.

    PubMed  PubMed Central  Google Scholar 

  38. Barrueto F Jr, Kirrane BM, Cotter BW, Hoffman RS, Nelson LS. Cardioactive steroid poisoning: a comparison of plant- and animal-derived compounds. J Med Toxicol. 2006;2(4):152–5.

    PubMed  PubMed Central  Google Scholar 

  39. Schoner W. Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem. 2002;269(10):2440–8.

    CAS  PubMed  Google Scholar 

  40. Staessen JA, Bianchi G. Adducin and hypertension. Pharmacogenomics. 2005;6(7):665–9.

    CAS  PubMed  Google Scholar 

  41. Bagrov AY, Shapiro JI. Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Clin Pract Nephrol. 2008;4(7):378–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs. 2007;7(3):173–89.

    CAS  PubMed  Google Scholar 

  43. Lam GK, Hopoate-Sitake M, Adair CD, Buckalew VM, Johnson DD, Lewis DF, et al. Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: a secondary analysis of the DEEP Trial. Am J Obstet Gynecol. 2013;209(2):119 e111–116.

    Google Scholar 

  44. Vithayathil MK, Edwards M. Comfrey herbal remedy causing second-degree heart block: do not be outfoxed by digitalis. BMJ Case Rep. 2016. https://doi.org/10.1136/bcr-2016-216995.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lin CC, Yang CC, Phua DH, Deng JF, Lu LH. An outbreak of foxglove leaf poisoning. J Chin Med Assoc. 2010;73(2):97–100.

    PubMed  Google Scholar 

  46. Wu IL, Yu JH, Lin CC, Seak CJ, Olson KR, Chen HY. Fatal cardiac glycoside poisoning due to mistaking foxglove for comfrey. Clin Toxicol (Phila). 2017;55(7):670–3.

    Google Scholar 

  47. Maffe S, Cucchi L, Zenone F, Bertoncelli C, Beldi F, Colombo ML, et al. Digitalis must be banished from the table: a rare case of acute accidental Digitalis intoxication of a whole family. J Cardiovasc Med (Hagerstown). 2009;10(9):727–32.

    Google Scholar 

  48. Sangle SA, Inamdar S, Deshmukh V. Cryptostegia grandiflora toxicity manifesting as hyperkalemia, complete heart block and thrombocytopenia. J Assoc Physicians India. 2015;63(5):79–81.

    PubMed  Google Scholar 

  49. Castello LM, Negro S, Santi F, Zanotti I, Vidali M, Bagnati M, et al. Accidental digitoxin intoxication: an interplay between laboratory and clinical medicine. Biochem Med (Zagreb). 2012;22(3):380–4.

    PubMed  PubMed Central  Google Scholar 

  50. Fitzgerald KT. Lily toxicity in the cat. Top Companion Anim Med. 2010;25(4):213–7.

    PubMed  Google Scholar 

  51. Romano GA, Mombelli G. Poisoning with oleander leaves. Schweiz Med Wochenschr. 1990;120(16):596–7.

    CAS  PubMed  Google Scholar 

  52. Nishioka Sde A, Resende ES. Transitory complete atrioventricular block associated to ingestion of Nerium oleander. Rev Assoc Med Bras (1992). 1995;41(1):60–62.

  53. Roberts DM, Buckley NA. Antidotes for acute cardenolide (cardiac glycoside) poisoning. Cochrane Database Syst Rev. 2006(4):CD005490.

  54. Goldman P. Herbal medicines today and the roots of modern pharmacology. Ann Intern Med. 2001;135(8 Pt 1):594–600.

    CAS  PubMed  Google Scholar 

  55. Whayne TF Jr. What should medical practitioners know about the role of alternative medicines in cardiovascular disease management? Cardiovasc Ther. 2010;28(2):106–23.

    CAS  PubMed  Google Scholar 

  56. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777–98.

    CAS  Google Scholar 

  57. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John’s wort. J Psychopharmacol. 2004;18(2):262–76.

    CAS  PubMed  Google Scholar 

  58. Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci. 2006;78(18):2131–45.

    CAS  PubMed  Google Scholar 

  59. Andelic S. Bigeminy–the result of interaction between digoxin and St. John’s wort. Vojnosanit Pregl. 2003;60(3):361–4.

    PubMed  Google Scholar 

  60. Stanton DT, Ankenbauer J, Rothgeb D, Draper M, Paula S. Identification and characterization of novel sodium/potassium-ATPase inhibitors by virtual screening of a compound database. Bioorg Med Chem. 2007;15(18):6062–70.

    CAS  PubMed  Google Scholar 

  61. Fuerstenwerth H. On the differences between ouabain and digitalis glycosides. Am J Ther. 2014;21(1):35–42.

    PubMed  Google Scholar 

  62. Marcus FI. Digitalis pharmacokinetics and metabolism. Am J Med. 1975;58(4):452–9.

    CAS  PubMed  Google Scholar 

  63. Smith TW. The basic mechanism of inotropic action of digitalis glycosides. J Pharmacol. 1984;15(Suppl 1):35–51.

    CAS  PubMed  Google Scholar 

  64. Hauptman PJ, Garg R, Kelly RA. Cardiac glycosides in the next millennium. Prog Cardiovasc Dis. 1999;41(4):247–54.

    CAS  PubMed  Google Scholar 

  65. Ewy GA. Digoxin: the art and science. Am J Med. 2015;128(12):1272–4.

    CAS  PubMed  Google Scholar 

  66. Yeh JY, Huang WJ, Kan SF, Wang PS. Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol. 2001;166(5):1937–42.

    CAS  PubMed  Google Scholar 

  67. Khan MI, Chesney JA, Laber DA, Miller DM. Digitalis, a targeted therapy for cancer? Am J Med Sci. 2009;337(5):355–9.

    PubMed  Google Scholar 

  68. Osman MH, Farrag E, Selim M, Osman MS, Hasanine A, Selim A. Cardiac glycosides use and the risk and mortality of cancer; systematic review and meta-analysis of observational studies. PLoS One. 2017;12(6):e0178611.

    PubMed  PubMed Central  Google Scholar 

  69. Lopez-Lazaro M, Palma De La Pena N, Pastor N, Martin-Cordero C, Navarro E, Cortes F, et al. Anti-tumour activity of Digitalis purpurea L. subsp. heywoodii. Planta Med. 2003;69(8):701–4.

    CAS  PubMed  Google Scholar 

  70. Blaustein MP, Robinson SW, Gottlieb SS, Balke CW, Hamlyn JM. Sex, digitalis, and the sodium pump. Mol Interv. 2003;3(2):68–72, 50.

    CAS  PubMed  Google Scholar 

  71. Gosselink AT, van Veldhuisen DJ, Crijns HJ. When, and when not, to use digoxin in the elderly. Drugs Aging. 1997;10(6):411–20.

    CAS  PubMed  Google Scholar 

  72. Ewy GA, Groves BM, Ball MF, Nimmo L, Jackson B, Marcus F. Digoxin metabolism in obesity. Circulation. 1971;44(5):810–4.

    CAS  PubMed  Google Scholar 

  73. Vohringer HF, Rietbrock N. Digitalis therapy in renal failure with special regard to digitoxin. Int J Clin Pharmacol Ther Toxicol. 1981;19(4):175–84.

    CAS  PubMed  Google Scholar 

  74. Ugowe FE, Jackson LR 2nd, Thomas KL. Racial and ethnic differences in the prevalence, management, and outcomes in patients with atrial fibrillation: A systematic review. Heart Rhythm. 2018. https://doi.org/10.1016/j.hrthm.2018.05.019.

    Article  PubMed  Google Scholar 

  75. Dickson VV, Knafl GJ, Wald J, Riegel B. Racial differences in clinical treatment and self-care behaviors of adults with chronic heart failure. J Am Heart Assoc. 2015. https://doi.org/10.1161/JAHA.114.001561.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Harjai KJ, Nunez E, Shah M, Newman J. Does racial bias exist in the medical management of heart failure? Clin Cardiol. 2002;25(10):479–83.

    PubMed  Google Scholar 

  77. Braunwald E. Effects of digitalis on the normal and the failing heart. J Am Coll Cardiol. 1985;5(5 Suppl A):51A–59A.

    CAS  PubMed  Google Scholar 

  78. Huang D, Cheng JW. Pharmacologic management of heart failure with preserved ejection fraction. Ann Pharmacother. 2010;44(12):1933–45.

    CAS  PubMed  Google Scholar 

  79. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314(24):1547–52.

    CAS  PubMed  Google Scholar 

  80. Sacubitril/valsartan (entresto) for heart failure. JAMA. 2015;314(7):722–723.

  81. Gheorghiade M, St Clair J, St Clair C, Beller GA. Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators. J Am Coll Cardiol. 1987;9(4):849–57.

    CAS  PubMed  Google Scholar 

  82. Chavey WE, Hogikyan RV, Van Harrison R, Nicklas JM. Heart failure due to reduced ejection fraction: medical management. Am Fam Physician. 2017;95(1):13–20.

    PubMed  Google Scholar 

  83. Chia N, Fulcher J, Keech A. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2)): an evidence-based mnemonic for the treatment of systolic heart failure. Intern Med J. 2016;46(6):653–62.

    CAS  PubMed  Google Scholar 

  84. McKelvie RS. Heart failure. BMJ Clin Evid. 2011. Aug 30. published online. pii: 0204.

  85. Kongkaew C, Sakunrag I, Jianmongkol P. Non-compliance with digoxin in patients with heart failure and/or atrial fibrillation: a systematic review and meta-analysis of observational studies. Arch Cardiovasc Dis. 2012;105(10):507–16.

    PubMed  Google Scholar 

  86. Dec GW. Digoxin remains useful in the management of chronic heart failure. Med Clin North Am. 2003;87(2):317–37.

    CAS  PubMed  Google Scholar 

  87. Opie LH. Digitalis reappraised: still here today, but gone tomorrow? S Afr Med J. 2014;105(2):88–9.

    PubMed  Google Scholar 

  88. Young JB. Do digitalis glycosides still have a role in congestive heart failure? Cardiol Clin. 1994;12(1):51–61.

    CAS  PubMed  Google Scholar 

  89. Slatton ML, Irani WN, Hall SA, Marcoux LG, Page RL, Grayburn PA, et al. Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll Cardiol. 1997;29(6):1206–13.

    CAS  PubMed  Google Scholar 

  90. Cayley WE Jr. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Am Fam Physician. 2004;69(1):71–2.

    PubMed  Google Scholar 

  91. Al-Khatib SM, Lapointe NA, Chatterjee R, Crowley MJ, Dupre ME, Kong DF, et al. Treatment of atrial fibrillation. Treatment of Atrial Fibrillation. Rockville (MD); 2013.

  92. Jelliffe RW. The role of digitalis pharmacokinetics in converting atrial fibrillation and flutter to regular sinus rhythm. Clin Pharmacokinet. 2014;53(5):397–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Macle L, Cairns J, Leblanc K, Tsang T, Skanes A, Cox JL, et al. 2016 focused update of the canadian cardiovascular society guidelines for the management of atrial fibrillation. Can J Cardiol. 2016;32(10):1170–85.

    PubMed  Google Scholar 

  94. Perez A, Touchette DR, DiDomenico RJ, Stamos TD, Walton SM. Comparison of rate control versus rhythm control for management of atrial fibrillation in patients with coexisting heart failure: a cost-effectiveness analysis. Pharmacotherapy. 2011;31(6):552–65.

    PubMed  Google Scholar 

  95. Chen Y, Cai X, Huang W, Wu Y, Huang Y, Hu Y. Increased all-cause mortality associated with digoxin therapy in patients with atrial fibrillation: an updated meta-analysis. Medicine (Baltimore). 2015;94(52):e2409.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Nikolaidou T, Channer KS. Chronic atrial fibrillation: a systematic review of medical heart rate control management. Postgrad Med J. 1004;2009(85):303–12.

    Google Scholar 

  97. Master J, Schweitzer P. Is there a role for digoxin in atrial fibrillation without heart failure? Cardiol J. 2009;16(5):483–6.

    PubMed  Google Scholar 

  98. Lane DA, Boos CJ, Lip GY. Atrial fibrillation (chronic). BMJ Clin Evid. 2015. May 20. published online. pii: 0217.

  99. Lane DA, Apostolakis S, Boos CJ, Lip GY. Atrial fibrillation (chronic). BMJ Clin Evid. 2011. Nov 10. published online. pii: 0217.

  100. Turakhia MP. Digoxin in atrial fibrillation?: leave it out of the medicine cabinet. J Am Coll Cardiol. 2018;71(10):1075–7.

    PubMed  Google Scholar 

  101. Jaspers Focks J, Brouwer MA, Wojdyla DM, Thomas L, Lopes RD, Washam JB, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ. 2016;353:i2868.

    PubMed  PubMed Central  Google Scholar 

  102. Weisse AB. A fond farewell to the foxglove? The decline in the use of digitalis. J Card Fail. 2010;16(1):45–8.

    CAS  PubMed  Google Scholar 

  103. Adams KF Jr, Butler J, Patterson JH, Gattis Stough W, Bauman JL, van Veldhuisen DJ, et al. Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. Eur J Heart Fail. 2016;18(8):1072–81.

    CAS  PubMed  Google Scholar 

  104. 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):871–8.

    CAS  PubMed  Google Scholar 

  105. Sameri RM, Soberman JE, Finch CK, Self TH. Lower serum digoxin concentrations in heart failure and reassessment of laboratory report forms. Am J Med Sci. 2002;324(1):10–3.

    PubMed  Google Scholar 

  106. Cosmi F, Tarquini B, Mariottoni B, Cosmi D. Digitalis, a drug to be scrapped? G Ital Cardiol (Rome). 2017;18(2):121–8.

    Google Scholar 

  107. Gonzalez Andres VL. Systematic review of the effectiveness and indications of antidigoxin antibodies in the treatment of digitalis intoxication. Rev Esp Cardiol. 2000;53(1):49–58.

    CAS  PubMed  Google Scholar 

  108. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs. 2006;6(2):77–86.

    CAS  PubMed  Google Scholar 

  109. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012;125(4):337–43.

    PubMed  Google Scholar 

  110. Kirrane BM, Olmedo RE, Nelson LS, Mercurio-Zappala M, Howland MA, Hoffman RS. Inconsistent approach to the treatment of chronic digoxin toxicity in the United States. Hum Exp Toxicol. 2009;28(5):285–92.

    CAS  PubMed  Google Scholar 

  111. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol. 1992;69(18):108G–118G (disc 118G–119G).

    Google Scholar 

  112. Schrickel JW, Schwab JO, Yang A, Bitzen A, Luderitz B, Lewalter T. “Torsade de pointes” in patients with structural heart disease and atrial fibrillation treated with amiodarone, beta-blockers, and digitalis. Pacing Clin Electrophysiol. 2006;29(4):363–6.

    PubMed  Google Scholar 

  113. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731–751.

  114. Mowry JB, Burdmann EA, Anseeuw K, Ayoub P, Ghannoum M, Hoffman RS, et al. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila). 2016;54(2):103–14.

    CAS  Google Scholar 

  115. Marino A, Giordano L, Ardu F. Digoxin poisoning: new prospects for therapy. G Ital Nefrol. 2017;34(2):82–7.

    PubMed  Google Scholar 

  116. Farcas A, Bucsa C, Sinpetrean A, Leucuta D, Mogosan C, Dumitrascu D, et al. Preventability analysis of adverse drug reactions detected in two internal medicine departments in Romania. Intern Emerg Med. 2014;9(2):187–93.

    PubMed  Google Scholar 

  117. Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364–77.

    CAS  PubMed  Google Scholar 

  118. de Vries M, Seppala LJ, Daams JG, van de Glind EMM, Masud T, van der Velde N, et al. Fall-risk-increasing drugs: a systematic review and meta-analysis: I. cardiovascular drugs. J Am Med Dir Assoc. 2018. https://doi.org/10.1016/j.jamda.2017.12.013.

    Article  PubMed  Google Scholar 

  119. Steiness E. Diuretics, digitalis and arrhythmias. Acta Med Scand Suppl. 1981;647:75–8.

    CAS  PubMed  Google Scholar 

  120. Manini AF, Nelson LS, Hoffman RS. Prognostic utility of serum potassium in chronic digoxin toxicity: a case-control study. Am J Cardiovasc Drugs. 2011;11(3):173–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Young IS, Goh EM, McKillop UH, Stanford CF, Nicholls DP, Trimble ER. Magnesium status and digoxin toxicity. Br J Clin Pharmacol. 1991;32(6):717–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Kolev KK. Digoxin—‘a friend or foe’. BMJ Case Rep. 2012. https://doi.org/10.1136/bcr.01.2012.5582.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Lewis RP. Clinical use of serum digoxin concentrations. Am J Cardiol. 1992;69(18):97G–106G (discussion 106G–107G).

    Google Scholar 

  124. Haber E. Antibodies and digitalis: the modern revolution in the use of an ancient drug. J Am Coll Cardiol. 1985;5(5 Suppl A):111A–117A.

    CAS  PubMed  Google Scholar 

  125. Lapostolle F, Borron SW, Verdier C, Arnaud F, Couvreur J, Megarbane B, et al. Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure. Intensive Care Med. 2008;34(8):1448–53.

    PubMed  Google Scholar 

  126. Hess T, Riesen W, Scholtysik G, Stucki P. Digitoxin intoxication with severe thrombocytopenia: reversal by digoxin-specific antibodies. Eur J Clin Invest. 1983;13(2):159–63.

    CAS  PubMed  Google Scholar 

  127. Vibe Nielsen S, Petersen RH. Antidigitalis Fab-fragment for treating poisoning from a foxglove plant. Ugeskr Laeger. 2013;175(24):1701–2.

    PubMed  Google Scholar 

  128. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365(24):2268–76.

    CAS  PubMed  Google Scholar 

  129. Hohnloser SH, Halperin JL, Camm AJ, Gao P, Radzik D, Connolly SJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol. 2014;7(6):1019–25.

    CAS  PubMed  Google Scholar 

  130. Frommeyer G, Milberg P, Schulze Grotthoff J, Dechering DG, Kochhauser S, Stypmann J, et al. Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias. Europace. 2015;17(8):1300–8.

    PubMed  Google Scholar 

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Acknowledgements

The author thanks Colleen McMullen, MA, MBA, for her excellent editorial critique.

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  1. Gill Heart and Vascular Institute, University of Kentucky, 326 Wethington Building, 900 South Limestone Street, Lexington, KY, 40536-0200, USA

    Thomas F. Whayne Jr

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Thomas F. Whayne, Jr, MD, PhD, has no conflicts of interest that are directly relevant to the content of this review.

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Whayne, T.F. Clinical Use of Digitalis: A State of the Art Review. Am J Cardiovasc Drugs 18, 427–440 (2018). https://doi.org/10.1007/s40256-018-0292-1

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