Long-term Digoxin Use Linked to VT/VF Risk in HF Patients

In patients with heart failure with reduced ejection fraction (HFrEF) who have an implantable cardioverter-defibrillator (ICD), the use of digoxin may increase the risk of ventricular tachyarrhythmia and death, new research cautions.

In a study of thousands of HF patients enrolled in four different trials involving automatic cardioverter-defibrillator implantation, those on digoxin had a 48% increased risk of device-detected ventricular tachycardia/ventricular fibrillation (VT/VF) and a 37% increased risk of all-cause death over 4 years compared with patients not taking digoxin, researchers report in the Journal of the American College of Cardiology: Clinical Electrophysiology.

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To TCTMD, lead author Amole Ojo, MD (University of Rochester Medical Center, NY), said he and his colleagues became interested in the topic after one of their HFrEF patients developed a ventricular arrhythmia while on digoxin and they could find only limited data on an association between digoxin use and increased risk of tachyarrhythmias in HF patients.

While a link between digoxin use and increased risk of death in these HFrEF patients was not surprising and is within range of what others have reported, Ojo said what did surprise the investigators was the magnitude of the increased risk of VT/VF that they saw in their study.

“I was not expecting it to be as high as that,” he said. “Based on these findings, I would not use digoxin in the long term.”

Based on these findings, I would not use digoxin in the long term. Amole Ojo

In an accompanying editorial, Pattara Rattanawong, MD, and E. Kevin Heist, MD, PhD (both Massachusetts General Hospital/Harvard Medical School, Boston, MA), say despite the nostalgia that some clinicians still have for digoxin—one of the oldest drugs in continuous clinical use—the findings from this study and others that have shown a association between digoxin and mortality in patients with atrial fibrillation (AF) call for a reassessment of routine use of digoxin in HF management.

“The precise mechanism behind the observed association between digoxin use and heightened risk of ventricular arrhythmias and mortality remains uncertain,” they write. “Potential factors include subclinical digoxin toxicity, which may induce ventricular arrhythmias through mechanisms, such as reentry or triggered membrane activity, including delayed afterdepolarizations.”

One caveat they point to, however, is that the patients included in the study were enrolled between 1997 and 2011, which raises questions about the generalizability of findings to contemporary practice, noting that the “landscape of HF management has evolved significantly since then,” with newer agents such as sacubitril/valsartan (Entresto; Novartis) and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Ojo agreed, adding that digoxin has become mostly outdated in favor of newer drugs, although it is still a reasonable consideration in some situations, such as for short-term use in a patient in the ICU with AF and low BP.

“In that situation where you cannot use all of the medications we normally use, maybe you use digoxin temporarily at that point,” he said. “But once things improve, they should be switched to other medications. If rate is still not controlled, [you can] put in a pacemaker and do AV node ablation . . . and people do well with that.”

More Events and Death Seen

For the study, Ojo and colleagues looked at patients enrolled in the four landmark Multicenter Automatic Defibrillator Implantation Trials (MADIT). Of the 4,499 patients, 26% were on digoxin (mean age 64 years; 26% female; 14% Black).

Compared with patients not on digoxin, more of those on the drug had history of atrial arrhythmias and LVEF of 25% or lower.

In addition to greater risks of VT/VF, the digoxin group also had increased risks of severe life-threatening arrhythmic events including fast VT/VF (HR 1.58; 95% CI 1.31-1.92) and recurrent VT/VF (HR 1.46; 95% CI 1.17-1.82) compared with the group not on digoxin. The digoxin group had an average of 1.5 VT/VF events per patient over the 4-year follow-up period, versus an average of 1.1 per patient in the nondigoxin group (P < 0.001).

The investigators also looked at appropriate and inappropriate ICD shocks, finding that the digoxin group had a higher incidence of appropriate shocks over the follow-up period than the nondigoxin group (25% vs 12%; P < 0.001), with no differences seen between the groups in terms of inappropriate ICD shocks.

The cumulative probability of death was 20% in those on digoxin and 14% in those not on digoxin (P < 0.001). Looking at the cumulative probability of the composite endpoint of VT/VF or death over the follow-up period, the digoxin group had a 48% probability versus 31% for those not taking digoxin (P < 0.001).

Ojo and colleagues note that while it is possible that digoxin dosing impacted outcomes, that information was not available to them.

According to Rattanawong and Heist, another limitation of this research is the heterogeneous nature of HF patient populations, which complicates data interpretation, particularly in a nonrandomized study like this one.

“Baseline differences between digoxin users and nonusers, despite attempts at propensity adjustment, may introduce residual biases,” they write. “Factors such as disease severity, comorbidities, and concomitant medications could confound the observed associations between digoxin use and clinical outcomes.”