Dosing Crucial for Digoxin, Warfarin Safety

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Digoxin was shown to be dangerous at high levels for atrial fibrillation (Afib) patients in a randomized trial. Meanwhile, another study suggested the benefit of genotyping for better warfarin (Coumadin) dosing.

Among digoxin users, baseline serum concentrations of 1.2 ng/mL or higher were independently related to death (adjusted HR 1.56, 95% CI 1.20-2.04), according a subanalysis of the ARISTOTLE trial presented here at the annual American College of Cardiology meeting.

For every 0.5 ng/mL increase in baseline digoxin, there was a 20% increase in odds of death at 1 year (adjusted HR 1.19, 95% CI 1.07-1.32), reported Renato D. Lopes, MD, PhD, of the Duke Clinical Research Institute in Durham, N.C.

"In patients with Afib already taking digoxin, monitoring its serum concentration may be important, targeting blood levels <1.2 ng/mL," the investigators suggested.

"Follow the levels more closely than ever before, maybe monthly instead of every 6 months," suggested Jagmeet P. Singh, MD, PhD, of Boston's Massachusetts General Hospital.

A discussant who was not involved in ARISTOTLE, Singh added in a press conference that arrhythmia monitoring may also be called for to see if digoxin has any pro-arrhythmic effects.

New digoxin users also had higher mortality risk compared with matched controls (adjusted HR 1.78, 95% CI 1.37-2.31). This mortality disadvantage was observed in the heart failure cohort (adjusted HR 1.58, 95% CI 1.12-2.24) and even more prominent in the non-heart failure group (adjusted HR 2.07, 95% CI 1.39-3.08).

Those newly placed on digoxin also exceed controls in terms of sudden cardiac death (adjusted HR 4.01, 95% CI 1.90-8.47).

"In the absence of randomized trial data showing its safety and efficacy, digoxin should not be prescribed for patients with Afib, particularly if symptoms can be alleviated with other treatments," the researchers argued.

ARISTOTLE was a trial of 18,201 Afib patients with at least one other risk factor for stroke randomized to apixaban (Eliquis) or warfarin. The present analysis was a biomarker substudy of those who got blood samples taken at baseline (n=14,892).

GIFT: Genotyping Helps

During the same ACC late-breaking session, the GIFT trial showed that genotyping-assisted dosing for warfarin worked better than the conventional, clinically-guided approach.

When participants undergoing elective knee or hip replacement surgery (n=1650) were randomized to pharmacogenetic dosing or a clinical algorithm for dosing of prophylactic warfarin, combined adverse outcomes were less frequent in the genotyping group (10.8% versus 14.7%, RR 0.73, 95% CI 0.56-0.95). International normalized ratio (INR) drove the difference among the individual components of the composite.

• Major bleeding within 30 days (0.25% versus 1.01%, P=0.062)
• INR≥4 within 30 days (6.9% versus 9.8%, P=0.041)
• Death within 30 days (4.1% versus 4.8%, P=0.48)
• Venous thromboembolism within 60 days of arthroplasty (0% versus 0%, P=1.00)

Overall, the genotype group had better INR control during days 4 to 28 of warfarin therapy (time in the therapeutic range 54.7% versus 51.3%, P=0.004) -- especially for high-risk patients (55.5% versus 48.4%, P=0.0002), according to Brian F. Gage, MD, of Washington University in St. Louis.

"The GIFT trial is an example of personalized medicine," Gage said. "If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right, from the get-go, we're less likely to have the patient overdose and can lower the risk of complications," Gage said as reported by the American College of Cardiology.

"I think the fact that we have a reduced risk of major bleeding by 27% shows genotype-guided dosing is beneficial," said Singh at the press conference.

In the trial, genotyping (largely with the GenMarkDx eSensor) was done at multiple sites, with samples processed at a central laboratory prior to surgery. Dosing was done via WarfarinDosing.org.

"Dosing algorithms from WarfarinDosing.org should be integrated into electronic medical records," the GIFT investigators suggested.

But is this example of personalized medicine truly ready for prime time?

"It is disappointing that clinical events were not lowered by the intervention," Kim A. Eagle, MD, of the University of Michigan in Ann Arbor, commented to the ACC. "Until genetic-based management is shown to really impact patient outcomes, the cost of routine genetic testing is questionable."

On top of that, Singh's concern was that the subgroup of patients undergoing hip and knee replacements may not be representative of other patients, such as those who have valve surgery. "We should be conservative when we extrapolate these results," he said.