Is the flower of physic withering?

Digitalis lanata

In 1775 William Withering began his clinical investigation into the medicinal properties of the foxglove. Ten years later he published his results. “I soon found” he says, “that the foxglove is a very powerful diuretic of advantage in every species of dropsy except the encysted, and that it has a power over the motion of the heart to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends.”

In the 1890s James Mackenzie advanced clinical knowledge of digitalis. He used the ink polygraph to recorded the venous and arterial pulses simultaneously and showed that the irregular pulse of atrial fibrillation was always associated the absence of the atrial wave in the venous pulse trace. In his clinical studies Mackenzie found that digitalis was particularly effective in patients with heart failure associated with atrial fibrillation. At the same time, chemists were trying to extract and purify the active components in the foxglove leaf. In 1869 crystalline digitoxin was isolated and shown to have similar medicinal properties to digitalis leaf extract. A similar substance was discovered in 1928 and called gitoxin. It was then reported that the leaf of digitalis lanata which grew in the Danube Valley was more than four times as potent as standard digitalis. In 1929 some of the dried leaves were brought to the Wellcome Research Laboratories in Beckenham in Kent where much work had already been done on the purple foxglove to work out methods of extracting and purifying the chemical components. Using the digitalis lanata leaves chemists found a new substance, which formed tiny canoe-shaped crystals, and they named it digoxin.

Digoxin became more or less the standard treatment for heart failure associated with atrial fibrillation and also in patients with normal cardiac rhythm. Given by mouth at a dose of 1mg per day or intravenously for more rapid effect it was particularly effective in slowing the heart rate also had diuretic activity relieving the symptoms of congestive heart failure. At a time when the only other therapy was bed rest and mercurial diuretics the effects of digoxin were dramatic and important.

Digoxin was introduced into cardiology before clinical trials were the norm and is still part of the current ACC/AHA guidelines. These state that digoxin can be beneficial in patients to decrease hospitalisations for heart failure. What is the evidence behind this recommendation? There are a series of old clinical trials conducted between 1977 and 1993 examining the effects of dioxin in chronic heart failure. Most of them are small and the only large randomised study is the Digitalis Investigation Group (DIG) study. In DIG patients with an ejection fraction of 45% or less were randomised to digoxin or placebo in addition to diuretics and angiotensin-converting enzyme inhibitors. Digoxin did not reduce mortality but did decrease the rate of hospitalization heart failure.

Trying to evaluate the place of digoxin is difficult since at the time of the DIG trial β-blockers, spironolactone / eplerenone, ibvabradine or resynchronisation therapy were not recognised treatments for heart failure. So we simply don't know if digoxin is beneficial in patients today, worse still, could it be harmful? 

In the Valsartan Heart Failure Trial digoxin was associated with higher risk of death and hospitalization for heart failure. The only randomised trial conducted recently showed that in severely ill patients awaiting cardiac transplantation for advanced heart failure digoxin increased risk in death. A post hoc analysis of the DIG trial also showed higher risk of death among women and in a recent study published this year in patients with systolic heart failure showed that digoxin was again associated with a significantly increased mortality.

These findings should cause us to reconsider the role of digoxin in the management of patients in sinus rhythm with systolic heart failure. Perhaps after more than 200 years of clinical use it might be time to say farewell to the foxglove as the flower of physic withers.

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