Digoxin benefits questioned once more

February 19, 2003

New Haven, CT - A new post hoc analysis of the Digitalis Investigation Group (DIG) trial has found that serum digoxin concentrations (SDCs) usually considered within the normal therapeutic range may in fact be harmful[1]. SDCs of 1.2 ng/mL or greater are associated with increased mortality in men with heart failure, the researchers found.

"Our study is the first, to our knowledge, to examine the association of different SDCs and major clinical end points," say Dr Saif S Rathore and colleagues (Yale University School of Medicine, New Haven, CT) in their report in the Journal of the American Medical Association this week. Senior author Dr Harlan M Krumholz (Yale University, New Haven, CT) told heartwire : "What we have shown is that levels of digoxin that are usually considered within the 'normal' range may cause harm. Heart failure experts have been saying for a long time that we should be dosing digoxin at lower levels."

What we have shown is that levels of digoxin that are usually considered within the 'normal' range may cause harm.

Rathore, Krumholz, and colleagues did not participate in the original DIG trialwhich was conducted from 1991 to 1995but instead accessed the complete data set through the NIH data distribution agreement. They have previously used data from the DIG trial to look at digoxin in women, who constituted less than a quarter of the trial population. As reported by heartwire , they found that females receiving digoxin had a rate of death that was more than 4% higher than that of women taking placebo, suggesting that the drug may in fact be harmful in women.

Following these findings in women, which were published in the New England Journal of Medicine last October, they decided to examine the relationship between SDC and outcomes, Krumholz explained. Because SDCs were available for only a small number of women, they decided to restrict the analysis to men. Of a total of 3782 men in the DIG trial with LVEF of 45% or less, 1171 had SDCs measured 1 month after randomization to digoxin therapy. These were divided into 3 groups—SDC between 0.5 and 0.8 ng/mL (n=572), SDC between 0.9 and 1.1 ng/mL (n=322), and SDC of 1.2 ng/mL or greater (n=277)—and were compared with the 2611 patients randomly assigned to receive placebo.

Evidence that levels within the normal range may be harmful

Krumholz said: "What we felt was that the target SDC of between 0.8 ng/mL and 2.0 ng/mL in the DIG trial may have been too high. People have been saying that for a while without any evidence." Even after adjusting for confounding factors, the researchers found the association between higher mortality and SDC of 1.2 ng/mL or greater persisted (see table). "Our findings...suggest that the effectiveness of digoxin therapy in men with heart failure...may be optimized in the SDC of 0.5 to 0.8 ng/mL," they state.

Adjusted outcomes and hazard ratios by SDCs

Adjusted outcomes* Placebo HR** (95% CI) by SDC 0.5-0.8 ng/mL HR (95% CI) by SDC 0.9-1.1 ng/mL HR (95% CI) by SDC 1.2 ng/mL or greater
All-cause Referent 0.80 (0.68-0.94) 0.89 (0.74-1.08) 1.16 (0.96-1.39)
Cardiovascular Referent 0.86 (0.72-1.02) 0.93 (0.76-1.14) 1.21 (0.99-1.47)
Worsening heart failure Referent 0.66 (0.49-0.89) 0.86 (0.63-1.17) 0.95 (0.69-1.31)
All-cause Referent 0.83 (0.74-0.93) 1.02 (0.89-1.18) 0.90 (0.77-1.04)
Worsening heart failure Referent 0.56 (0.46-0.67) 0.74 (0.60-0.92) 0.65 (0.52-0.82)
*Adjusted for age; race; body mass index; LVEF; NYHA class; cardiothoracic ratio; number of HF signs and symptoms; systolic BP; heart rate; estimated glomerular filtration rate; duration of HF; primary cause of HF; history of MI, angina, diabetes, and hypertension; prior use of digoxin; and use of potassium-sparing diuretics, all other diuretics, ACE inhibitors, nitrates, hydralazine, and other vasodilators
**HR=hazard ratio

"Given that no study has demonstrated any substantive clinical benefit for SDCs higher than 0.8 ng/mL, prudent practice would support an SDC of 0.5 to 0.8 ng/mL as a revised therapeutic range," the researchers say. But the feasibility of achieving SDCs within this range in daily clinical practice "is unclear," they note.

Digoxin doses are "guessed"; is it beneficial at all?

Echoing comments he made last October at the time of publication of the data on women in DIG, Krumholz says that current guidelines do not provide much guidance to the correct use of digoxin. "A lot of people just make a guess as to the correct dose." He feels this should be formalized in a similar way to how warfarin is dosed. Also, monitoring of digoxin levels is performed at best intermittently, he believes. "And then, most people are monitoring it to avoid direct toxicity rather than trying to use SDC to optimize effectiveness of the drug."

"If our results are true, this suggests that digoxin ought to be monitored like Coumadin [warfarin] to ensure that levels stay within a fairly narrow therapeutic range," he says. However, he wonders whether in practice it will be possible to keep people within this range. "At the very least these new findings warrant a reexamination of current guidelines, and they raise questions about the safety of digoxin at the higher end of therapeutic levels," he adds.

But going a step further, he again questions the need for such widespread use of digoxin. "It's a very commonly prescribed drug, with no immediate side effects, which people feel comfortable with because it's been around for 200 years." But, he adds, "If you put things in perspective, the only significant trial of digoxinDIGwas negative." (The main DIG trial showed no reduction in the rate of the primary outcome of the trialdeath from any causebetween patients taking digitalis or placebo. But rate of hospitalizations for worsening heart failure, a secondary end point of the trial, was significantly reduced.)

When a patient has an underlying condition with a high rate of death, such as heart failure, Krumholz says any additional mortality associated with high therapeutic levels of digoxin can easily go unnoticed: "Are you really going to notice if 25% of your patients die rather than 20%?" Krumholz adds that digoxin's benefits may in fact be mediated via neurohormonal modulation, with minimal inotropic-associated risks at lower SDCs. So he wonders, "In the era of beta blockers [in heart failure], is digoxin beneficial at all?"


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