It is not as though we weren't warned: In 1785, Sir William Withering declared that the extract from the plant foxglove, sometimes called digitalis, was not a perfect drug.“ Time will fix the real value upon this discovery,” he wrote.

It now seems that William Withering was a man ahead of his time.

His warning has recently been validated — albeit 230 years later. Stanford researchers have found that patients with the irregular heartbeat known as atrial fibrillation (AF) who were treated with the digitalis-derivative digoxin were more likely to die than those treated with other drugs.

People treated with digoxin were 1.2 times more likely to die than those prescribed other treatments. They also found that people taking digoxin had an increased risk of death regardless of age

The findings raise the question of whether or not patients should even be on digitalis, “These data challenge the current guidelines,” the lead author of the study, Mintu Turakhia, said in a press release.

The team analyzed the records of more than 122,000 patients from the U.S. Department of Veterans Affairs health care system who were diagnosed with AF between 2003 and 2008. Digoxin was prescribed for 23 percent of the patients.

The investigators found that people treated with digoxin were 1.2 times more likely to die than those prescribed other treatments. They also determined that people taking digoxin had an increased risk of death regardless of age; use of other drugs such as beta-blockers, amiodarone, or warfarin; or whether they had other conditions such as kidney disease, heart attack, or heart failure.

The findings were a surprise, Turakhia, an assistant professor of cardiology at Stanford and director of cardiac electrophysiology at the Veterans Affairs Palo Alto Health Care System, said in an email. The researchers had expected only to see an increased risk of death in patients who had reduced kidney function because that would confirm the results of previous studies.

What they saw instead was a consistent association between digoxin and decreased survival among patients who also had other diseases, including heart failure and prior heart attack. So these results are broadly generalizable across the spectrum of patients with AF, said Turakhia.

“We now know more about when digoxin should not be used rather than when it is likely to be safe.” This is in part because the only major randomized trial of digoxin was in patients with heart failure who did not have AF, he explained.

The current clinical guidelines on digoxin do advise using digoxin cautiously as second line therapy or in addition to other medications when those drugs do not work. At present, no studies confirm that these approaches are safe, either, Turakhia said.

The good news is that there are plenty of alternatives to digoxin. According to Turakhia, “Over the last 20 years, we have made extraordinary strides in the treatment of AF, and most of the time, we don’t need to rely on an old world remedy like digoxin.”

Beta blockers and calcium channel blockers work well to control heart rate in most patients with AF. In some patients, treatments to return the heart to its proper rhythm, such as antiarrhythmic drugs and catheter ablation, may be preferable to other therapies.

Future studies are needed to clarify why digoxin leads to increased mortality, Turakhia indicated. It's not likely that a large randomized controlled trials will be necessary, he said. “We now live in a new era of medicine, in which there will be more large-scale observational studies than mega-trials. We need to consider the context and uncertainty of the result, not just the result itself.”

The study is published online in the Journal of the American College of Cardiology.