The effect of digoxin on mortality and morbidity in patients with heart failure

Authors: Garg R, Gorlin R, Smith T, Yusuf S, for the Digitalis Investigation Group.
Source: New England Journal of Medicine. 336:525-33. February 20, 1997.
Institutions: multi-institutional in the United States and Canada.
Financial support: Glaxo Wellcome (supplied drug and placebo).



The efficacy of digoxin, particularly its effect on mortality, in patients with congestive heart failure in normal sinus rhythm has been debated for years. This large, randomized, placebo-controlled study was designed to look at the effect of digoxin on mortality and on hospitalization.


The study was divided into a main trial (6800 patients with CHF and an ejection fraction of 0.45 or less) and an ancillary trial (988 patients with CHF but with an EF greater than 0.45). The results presented here concern the main trial.


Authors' conclusion: "In clinical practice, digoxin is likely to affect the frequency of hospitalization, but not survival".


As noted by Milton Packer in an accompanying editorial, this study will give both sides of the digoxin debate fuel for their arguments. Those in favor of digoxin will be able to point to the beneficial effects on hospitalization noted here and to the lack of a deleterious effect on mortality (unlike other positive inotropes, which have been found to increase mortality). The anti-digoxin side will point to the lack of a positive effect on mortality (unlike ACE inhibitors, and perhaps beta-blockers). This study is thus unlikely to dramatically change any ingrained prescribing habits, but it does provide much-needed hard data for this long-standing controversy.

A note on combining endpoints

One objection I have to the way the results are presented here is the use of the combined endpoints "death or hospitalization for heart failure" and "death from heart failure or hospitalization for heart failure".

Combining endpoints always entails a loss of information. Nevertheless, it sometimes makes good sense to combine specific endpoints. When two or more events are of similar clinical importance and often occur as a trade-off or cannot be reliably distinguished, combining them makes perfect sense. Thus, when looking at various causes of death, the combined endpoint of "all-cause mortality" makes good sense, since it is not always possible to accurately determine the actual cause of death, and the clinical impact of death from one cause is very similar to that of death from another cause. What counts is "dead or alive"; whether dead from cardiovascular disease or another cause matters little to the patient. Another example of a useful combining of endpoints is "death or severe deficit at 6 months" when looking at thrombolytic therapy for stroke. Thrombolytic therapy for stroke might convert some patients who would have had a severe deficit to either a minor deficit or to death from intracerebral bleeding. Since a severe deficit after a stroke is an outcome that is at least in the same order of magnitude of severity as death, it makes sense to consider "death or severe disability" as a combined endpoint.

On the other hand, death is a substantially more serious outcome than non-fatal myocardial infarction, for example. Many studies of lipid-lowering therapy look at this combined endpoint (death or non-fatal MI), which makes little sense, in my opinion. Ten deaths plus one MI is not comparable to ten MI's plus one death. I suspect that the reason this combined endpoint is used is because many trials have shown a significant reduction in MI without being able to show a reduction in mortality. By using the combined endpoint, "death or MI", the beneficial effect on MI can be "extended" to the word death, making the results seem more impressive. But this is spin-doctoring. We are better served with the data on death and MI presented individually, not aggregated.

Similarly, in the study being reviewed here, the combined outcome of "death or hospitalization for heart failure" makes little sense. Ten deaths plus one hospitalization is not comparable to ten hospitalizations plus one death. The authors note that, in patients with more severe congestive heart failure, the effect of digoxin on the combined endpoint of "death from CHF or hospitalization for CHF" was stronger than in the overall study population. But this does not tell us whether there was a significant effect on mortality in this subgroup, or whether the stronger effect was due to a greater reduction in hospitalizations only. Perhaps the authors will publish another paper entitled "the effect of digoxin on mortality in patients with severe congestive heart failure", and we will then have the answer to this question.

February 27, 1997

Reader comments

Date: Fri, 28 Feb 1997
From: (Sergio Emanuel Kaiser)

Regarding combined endpoints for heart failure, I agree with you. However, in the example that you mentioned, death and non-fatal MI, we can also face this association in a different way: if death due to coronary disease and non-fatal MI share the same pathophysiological mechanism, then it would make sense to have them combined.

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