More Digoxin Cautions: Use in AF, Heart Failure Raises Mortality in Meta-analysis

Marlene Busko

May 13, 2015

FRANKFURT, GERMANY — Digoxin use was linked with a 29% increased risk of mortality in more than 235,000 patients with atrial fibrillation (AF) and with a 14% increased risk of death in more than 91,000 patients with congestive heart failure (CHF) during an average follow-up of 2.5 years, researchers report[1].

These findings by Dr Mate Vamos (JW Goethe University, Frankfurt, Germany) and colleagues, based on data from 19 contemporary studies of digoxin, were published online May 4, 2015 in the European Heart Journal.

Even though digoxin has been used for 200 years, only one study, the Digitalis Investigation Group (DIG) study in AF, which dates from the 1990s, was a randomized controlled trial. Therefore, according to the authors, until proper contemporary randomized trials with dose-adjusted digoxin are conducted, the drug "should be used with great caution (including monitoring plasma levels), particularly when administered for rate control in AF," the authors urge.

Indeed, a key take-away message for clinicians is "better think twice before prescribing digoxin," senior author Dr Stefan H Hohnloser (JW Goethe University) told heartwire from Medscape. There are good alternatives such as beta-blockers for rate control in AF, and therapy for congestive HF has "dramatically changed . . . compared with the time when the DIG trial was conducted," he added.

"Until proper randomized controlled trials are completed, digoxin should be used with great caution (including monitoring plasma levels), particularly when administered for rate control in AF," Vamos and colleagues stress. However, "patients should not stop their digoxin on their own but rather should consult with their cardiologists," Hohnloser cautioned.

How Safe Is Digoxin?

Digoxin slows conduction in the AV node during rest, which is why it is used in AF for rate control, and it is a positive inotropic drug, which is why it is used in CHF, Hohnloser explained. However, it can cause arrhythmias (both brady- and tachyrhythmias), it interacts with other medications, it has a narrow therapeutic window, and it may cause direct toxicity if overdosed, he added

Current European Society of Cardiology and US guidelines recommend considering digoxin in certain patients with HF or AF, but "in essence, these recommendations reflect the highly unsatisfactory data basis on which to judge the supposed benefits of digoxin," Vamos and colleagues write.

Recent studies suggested that digoxin may increase the risk of death.

To investigate this, Vamos and colleagues identified studies of digoxin published since 1993, comprising 326,426 patients: nine studies in patients with AF, seven in patients with CHF, and three in patients with both conditions.

In follow-up ranging from 0.83 to 4.7 years, digoxin use was associated with an increased risk of all-cause mortality.

Risk for All-Cause Mortality, Patients Receiving vs Not Receiving Digoxin*

Reason for digoxin HR (95% CI) P
AF 1.29 (1.21–1.39) <0.01
HF 1.14 (1.06–1.22) <0.01
AF or HF 1.21 (1.07–1.38) <0.01
AF=atrial fibrillation
*After controlling for multiple confounders

"Looking at recent [novel oral anticoagulant] NOAC trials, for example, digoxin is used in approximately 20% to 30% of AF patients, [and it probably] is used less commonly in CHF patients in sinus rhythm," Hohnloser said.

When digoxin is used, to maximize patient safety, it is important to monitor patient's serum digoxin levels and be aware of harmful drug-drug interactions of digoxin with antiarrhythmic drugs such as amiodarone or dronedarone, according to Hohnloser. He prescribes digoxin "only very occasionally if I feel that I have no other option."

Hohnloser reports receiving consulting fees from Bayer Healthcare, Boehringer Ingelheim, Gilead, Johnson & Johnson, Medtronic, Pfizer, St Jude Medical, and Sanofi. He received lecture fees from Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb, Pfizer, St Jude Medical, Sanofi, and Cardiome outside the submitted work. Disclosures for the coauthors are listed in the article.


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