The effect of digoxin on survival in patients with heart failure: an answer at last?

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The effect of digoxin on survival in patients with heart failure: an answer at last?

J. R. Hampton, Division of Cardiovascular Medicine, Universital Hospital Nottingham, Queen´s Medical Centre, Nottingham

William Withering described the value of an extract of the foxglove for 'the cure of dropsy' in 1785, and for about 150 years digitalis was the only effective remedy for treating heart failure. With the introduction of the mercurial and then the thiazide diuretics, digitalis became considered to be less important, perhaps especially in the United Kingdom, and there were doubts whether it had any useful effect other than the control of the ventricular rate in patients with atrial fibrillation. A long series of studies - mainly involving the withdrawal of digoxin from treated patients - left doubt whether digoxin improved exercise time in patients with heart failure, and eventually evidence accumulated suggesting that it probably does not have any useful effect . There has been fairly convincing evidence from clinical trials (the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme, RADIANCE , and the Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin, PROVED ) that worsening heart failure and hospitalization occur less often in patients treated with digoxin, but the main concern about digoxin has been that it might actually increase fatality in patients with heart failure.

There has for many years been speculation that treatment with digoxin after myocardial infarction is associated with an increased risk of death. It has always been difficult to determine whether this was simply a reflection of the fact that patients with heart failure after myocardial infarction are at higher risk, but at least one study has identified digoxin therapy as having an independent deleterious effect. Furthermore, treatment with a range of unrelated compounds known to increase cardiac performance and to improve heart failure symptoms has been shown to be associated with an increase in fatality: the list of such treatments includes xamoterol , milrinone , enoximone , flosequinan and ibopamine . A trial specifically designed to study the effect of digoxin on mortality in patients with heart failure but who were in sinus rhythm was therefore of extreme importance, and the results of what is usually referred as the DIG Trial have now been published . In the main part of this trial 6800 patients with clinically-diagnosed heart failure and who had a left ventricular ejection fraction (LVEF) of less than 45% were randomly allocated on a double blind basis to treatment with digoxin or placebo. In a smaller parallel study, patients with heart failure but who had a higher ejection fraction were similarly randomised. The primary outcome was mortality, and in the main part of the trial there were during an average follow-up of 37 months 1181 deaths (34.8%) among the patients with digoxin and 1194 deaths (35.1%) among those allocated to placebo treatment. The effect of digoxin was therefore neutral so far as the main trial endpoint was concerned.

However, the trial outcomes that were defined as 'secondary' are of equal interest. These outcomes included death or hospitalization from worsening heart failure, and both of these were reduced by digoxin treatment.

In the digoxin group 394 deaths were attributed to worsening heart failure, compared to 449 in the placebo group (risk ratio 0.88, 95% confidence interval 0.77 - 1.01, p = 0.06). There were, however, a few more deaths from all cardiovascular causes in the digoxin group (1016 deaths, compared with 1004 in the placebo group) and the two treatment groups had nearly identical outcomes in total mortality because there were more deaths due to cardiac causes other than heart failure in the digoxin group (508 compared with 444 in the placebo group). These non-heart failure deaths, which were not described in detail, included those due to sudden death, arrhythmias, myocardial infarction, and cardiac surgery.

Significantly fewer patients in the digoxin group (910) than in the placebo group (1180) were admitted to hospital because of heart failure (risk ratio 0.72, 95% confidence interval 0.66 - 0.75, p less than 0.001).

The results of the DIG trial can therefore be interpreted in different ways, and the effect of the trials on clinical practice has to depend on this interpretation. Strictly speaking, all the trial showed (from its primary endpoint) was that digoxin had no effect on mortality in heart failure. However, it is not unreasonable to go further and accept that digoxin reduced deaths and hospital admissions due to heart failure itself; but if we accept this we must also accept that digoxin has an unwanted effect in increasing cardiac deaths involving mechanisms other than heart failure. Since hospitalization due to heart failure implies an increased severity of symptoms, most patients with heart failure would probably prefer to be treated with digoxin, knowing that their symptoms should be improved even though their mode of death (but not their likelihood of death) might well be changed.

The DIG trial does not help us to decide whether or not digoxin should remain the treatment of choice in patients with atrial fibrillation, for such patients were excluded from the study. There are alternative ways of controlling the ventricular rate in atrial fibrillation (including drugs such as verapamil, diltiazem, amiodarone etc.) but how these might compare with digoxin in their effect on survival is completely unknown.

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