Digoxin takes the rap again as yet another review goes to prove increased risk of death associated with the drug used for long to treat heart disease.

Researchers from the JW Goethe University in Frankfurt saw the heightened risk, particularly in those being treated for atrial fibrillation (AF), in a large study covering over 300,000 patients.

The study is published online in the European Heart Journal.

The systematic review and meta-analysis of all studies published in peer-reviewed journals between 1993-2014 looked at the effects of digoxin on death from any cause in heart patients.

An overall 21% increased risk of death from any cause was seen in those treated with digoxin compared to patients who were not receiving this treatment.

The risk was 29% for the group of AF patients and 14% for congestive heart failure (CHF) patients when compared to patients not receiving the drug.

Stefan Hohnloser, Professor of Cardiology at the university, who led the study, said: "Definite evidence can only come from results of randomised controlled trials. However, next to these, carefully performed meta-analyses provide the best clinical guidance and serve to generate hypotheses that need to be tested prospectively. Our analysis, together with evidence from other studies, all point in the same direction: there is harm associated with the use of digoxin."

There has only been one prospective randomised controlled trial of digoxin, which was carried out in 6,800 CHF patients, and none in AF patients.

The drug has a narrow dose range at which it is effective and beyond which it can be dangerous. Given the unsatisfactory data basis to judge digoxin, the researchers hence call for randomised controlled trials of digoxin.

Until such proper randomised controlled trials are completed, digoxin should be used with great caution particularly when administered for rate control in AF, they say.

The researchers identified 19 relevant studies that included a total of 326,426 patients (235,047 AF and 91,379 CHF patients).

The risk from digoxin can be made worse by interactions with other drugs, the researchers say pointing to a recent trial of dronedarone in AF patients that had to be stopped prematurely following many deaths.

Most deaths were among patients who had also received digoxin at the same time.

Digoxin is extracted from the foxglove plant (digitalis) and it helps the heart beat more strongly and with a more regular rhythm. It is commonly used in patients with atrial fibrillation (an irregular heartbeat) and also in patients with heart failure.

Experts have been cautioning against the use of digoxin except in some cases. Beta blockers or calcium channel blockers have been suggested as a better alternative.