Men with higher blood levels of digoxin (another name for the drug) had a greater risk of death than those with lower levels, says a report on the Digital Investigation Group (DIG) study in the Feb. 19 Journal of the American Medical Association.
Digitalis, derived from the foxglove plant, has been used to treat heart conditions for centuries, but the U. S. Food and Drug Administration gave approval for its use against heart failure only after the DIG trial was done in the 1990s.
The new report, derived from analysis of DIG trial data, is important "because it has the potential for really affecting practice," says Dr. Harlan Krumholz, a professor of medicine at the Yale School of Medicine and senior author of the study. "If there is a beneficial effect of digitalis, it appears at levels in the blood that are lower than what is typically done."
Some heart failure experts have reached a consensus that blood digoxin levels should be low, Krumholz says, but "I know from clinical experience and talking to people and reading the literature that generally there is not an emphasis on getting digoxin levels low. This article presents evidence that we should be treating at lower levels."
Last year, Krumholz led another study on digitalis finding that it might do more harm than good in women.
The DIG trial was designed to keep blood levels in the range of 0.5 to 2.0 nanograms per liter (a nanogram is a billionth of a gram) not for any clinical reason but because toxic effects of digoxin appear above that upper level, the journal report says. Since the initial publication, "concerns have been raised about the relative efficacy of serum digoxin levels great than 1.0 nanogram per liter," it says.
The new analysis looked at 3,782 men who were treated in the trial, dividing them into three groups on the basis of serum digoxin levels -- from 0.5 to 0.8 nanograms per liter, 0.9 to 1.1 nanograms per liter, and 1.2 nanograms per liter and higher.
Men with blood levels in the 0.5 to 0.8 range had a 6.3 percent lower risk of death than those getting a placebo. However, there was no reduction in risk for men in the 0.9 to 1.1 range, and an 11.8 percent higher death rate for those whose blood levels were 1.2 nanograms and higher, compared to those getting a placebo.
It's important to note the study looked at blood levels, not at the doses given patients, Krumholz says. The same dose can produce different blood levels, depending on patient characteristic, he says. For example, an older person with reduced kidney function should get a lower dose.
"Everything that Dr. Krumholz says makes sense," says Dr. Randall C. Starling, director of heart transplant services at the Cleveland Clinic. "This has added additional information and understanding on the dose-response level, as well as breaking it down to looking all at kinds of patients."
Blood levels are so important that heart failure patients taking digitalis should have periodic blood tests, in the same way that patients taking the blood thinner warfarin do, Krumholz says. In both cases, variations in blood levels could be clinically significant.
Such frequent tests may not be necessary, says Starling, but "the drug does have to be carefully monitored."
Asked if the report would change the way he practices, Starling says simply, "yes, it will."