No, We Should Not Denounce Digoxin

The Study of the Week goes back in history today to look at the DIG trial. You might be surprised.

William Withering first used digitalis in 1798. Wikipedia describes it as the beginning of modern therapeutics. FDA approved digoxin for use in 1998. Since then there has been controversy over its use.

The only time I’ve ever been a protagonist in a debate, has been my defense of digoxin as a useful drug.

In recent years, a large number of observational studies have been published—most of which associate dig use with increased death rates. The inherent problem with these studies is that sicker patients receive the drug, and this selection bias mars interpretation of the results.

Digoxin is an inexpensive generic medicine taken once daily. Briefly, It is a channel blocker and leads to increased calcium in the cardiac cell. This results in two effects: a stronger contraction (positive inotropy) and a slower rate, especially during AF.

The DIG Trial

The hypothesis of the DIG trial was that digoxin would reduce mortality vs placebo in patients with heart failure due to a reduced ejection fraction. Patients could be included if they had a LVEF < 45% though the mean LVEF of enrolled patients was 28%. The average age of patients was 63 years and most were men (78%).

The recommended dosing of digoxin came via an algorithm based on age, sex, weight and kidney function—like we do today in our heads.

DIG was a large trial—randomizing about 3400 patients each to the drug or placebo arm. The primary endpoint was death. Follow-up averaged about three years.

Results

There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80).

Given the tight confidence intervals, long follow-up and large number of events, I might tiptoe into writing that there seems to be evidence of absence of a mortality effect from digoxin.

Now let me show you one of the least well known findings from the trial. I’ve made a slide of it. Digoxin significantly reduced hospitalizations due to heart failure (HHF), which was a secondary endpoint.

The trial was published in 1997, but 20 years on, the heart failure community now leans heavily on the ability of a new drug to reduce HHF.

Here is the slide with another comparison. I’ve added the HHF reduction seen with dapagliflozin in the DAPA-HF trial and the HHF reduction with sacubitril/valsartan seen in the PARAGON-HF trial (HFpEF).

My point is that the 28% reduction in HHF with digoxin is quite similar to the celebrated new drugs of today.

Let me show you something else. Milton Packer wrote the editorial for the DIG trial.

Here is how he described the reduction in HHF in DIG.

In the trial reported here, digoxin had no effect on mortality but reduced the risk of hospitalization by 8 percent. This reduction, though significant, is so small that physicians would avoid only 9 hospitalizations by treating 1000 patients with digoxin for one year.

He downplayed it by describing it in absolute terms. In the previous paragraph he wrote that it was hard to determine causes of death or hospitalization.

This framing is why I have argued that heart failure trialists tell us how their drugs reduce total hospitalizations. The DIG trialists gave us this info. And, indeed, digoxin did reduce total hospitalizations.

Look also at the proportion of hospitalizations. In 1997, HHF hospitalizations in the treatment arms were roughly 40% of total hospitalizations. (26/64%).

In the most recent HFpEF trials of SGLT2i drugs, (dapagliflozin in the DELIVER trial) total hospitalizations was not presented. In the EMPEROR-Preserved trial of empagliflozin vs placebo in HFpEF, total hospitalizations were reduced but the reduction did not reach statistical significance. More important though is that HHF now represents a much smaller proportion of total hospitalizations ( 16%).

This reduction is because the modern patient with heart failure is older and has more competing causes of illness. Competing causes of ill health (co-morbidity) need to be considered when translating trial data to patients. It also renders less important the old endpoint of heart failure hospitalization.

Summary:

Digoxin, like any drug, has to be used carefully. It has a narrow therapeutic window. Excess levels can cause toxicity. Yet I think we’ve grown quite careful with the drug.

When I trained at Indiana in the 1990s, about every fourth unknown ECG was a dig-toxic rhythm. I have not seen one in years. I am pretty sure young doctors could not identify a dig-toxic rhythm—because it’s so rare.

My point in this post is to highlight data over dogma.

When you look at the data—not listen to dogma—digoxin compares fairly well to the new heart failure drugs—many of which also have no effect on mortality and reduce only one reason to be hospitalized.

Digoxin has been less well studied for its use in atrial fibrillation. It slows the ventricular response rate without lowering blood pressure.

I feel somewhat reassured using the drug in this setting because in sicker patients (enrolled in DIG) there was no signal of harm. Though I agree we need more data for this indication.