Back Digoxin: the Good, the Bad, and the Ugly

Digoxin is over 200 years old and its use has been widespread for a very long time. It is mentioned in NICE, ESC and AHA guidance in AF or heart failure1,2,3,4. The pitfalls of digoxin toxicity are well known. However, there is increasing evidence that there may be a higher risk to its routine use than many of us might have thought. Patients treated with digoxin had an increased risk of all-cause mortality in two papers published in 2015, one in AF5, and one study looking at AF or heart failure6. Now a subset analysis of the ARISTOTLE trial7 presented at ACC 2017 found some thought provoking findings. About 40% of the AF patients in ARISTOTLE had heart failure and more than 30% were on digoxin, so a fair number were analysed for this new analysis at about 3,000 patients. The effect of digoxin on mortality was assessed. Patients who started digoxin were compared to controls who had not started digoxin, with an extensive list of variables matched between the groups, including renal function. They found that, overall, the digoxin patients had a 10% increase in mortality. In patients already taking digoxin at the start, the overall relationship between digoxin use and death was non-significant. However, it was a different story for those who were commenced on it: if they were started on digoxin during the study, there was a 78 percent increase in all-cause mortality and a 300% increase in the risk of sudden death with digoxin use. Most of these sudden deaths occurred within six months after starting digoxin, and this increase in mortality started to become apparent just weeks after starting.

Furthermore, digoxin levels were analysed in three ranges: <0.8 ng/mL, 0.8-1.1 ng/mL, and >1.1 ng/mL. For those patients with levels >1.1 ng/mL, there was a 56% increase in all-cause mortality. This did not appear to be simply related to renal function.

The main limitations of the study were the lack of randomisation and as always, the potential for unmeasured confounding variables.

The authors suggest a take home message: “Use digoxin as a last resort, and if you have to use digoxin, check blood levels and keep them ≤1.1 ng/mL.”

Food for thought. But when selecting that “food” for thought, perhaps don’t eat digitalis…

References

  1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893-2962. Abstract

  2. January CT, Wann LS, Alpert JS, et al; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-2104. Abstract

  3. National Institute for Health and Care Excellence (2014). Atrial fibrillation: the management of atrial fibrillation. NICE guideline (CG180). Available at https://www.nice.org. uk/guidance/cg180.

  4. National Institute for Health and Care Excellence (2010). Chronic heart failure: management of chronic heart failure in adults in primary and secondary care. NICE guideline (CG108). Available at https://www.nice.org.uk/guidance/cg108.

  5. Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation(ROCKET AF). Lancet 2015; 385(9985):2363–70.

  6. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J 2015;36:1831–8. doi:10.1093/eurheartj/ehv143.

  7. Lopes R, Gibson CM. ARISTOTLE: digoxin and mortality in patients with atrial fibrillation with and without heart failure: does serum digoxin concentration matter? Program and abstracts of the American College of Cardiology 66th Annual Scientific Session & Expo; March 17-19, 2017; Washington, DC. Late-breaking clinical trial.