Digoxin Safe in Heart-Failure Patients With AF in Danish Cohort

Marlene Busko

September 10, 2015

LONDON, UK — The use of digoxin was associated with a slightly improved survival but no difference in rate of rehospitalization in a new study based on a nationwide propensity-matched cohort of Danish patients with heart failure and atrial fibrillation (AF)[1]. Lead author Dr Christian Madelaire (Gentofte University Hospital, Copenhagen, Denmark) presented these findings in an oral session at the European Society of Cardiology (ESC) 2015 Congress.

"There seem to be a lot of feelings about this subject, and you get the impression that it sometimes comes down to 'religion,' so to speak," Madelaire told heartwire from Medscape, when asked about the ongoing debate about using this drug for patients with heart failure and AF. "I think clinical practice of today is going away from [using digoxin], and if we cannot get a clinical trial to show any significant effect on both safety and efficacy, then I think it is a drug of the past," he said.

Session comoderator Dr Alexandre Mebazaa (Paris Diderot University, France) told heartwire that "digoxin was a drug that was used a lot at the time when we didn't have all the long-lasting medications—beta-blockers, ACE inhibitors, and now LCZ696" (valsartan/sacubitril [Entresto, Novartis], the first angiotensin receptor-neprilysin inhibitor [ARNI] drug, approved in July).

Since those drugs were approved based on huge studies with very strong primary end points, "there is no way today heart-failure patients anywhere in the world wouldn't have these three or four or even five medications, [but] we don't know exactly what to do with digoxin on top of this," he said. "We should rethink—with this population with a lower mortality than before, in the context of multiple medications—whether digoxin still has a place."

"Who in daily practice in past 3 months put a heart-failure patient on digoxin?" Mebazaa asked the audience. A show of hands revealed that about 10% had done so, and in most cases digoxin was given for arrhythmia, rather than to improve contractility. A Canadian cardiologist commented that "a lot of digoxin use tends to be geographical." At his new institution, they use digoxin for AF but also for patients in sinus rhythm with class 3 or 4 heart failure who are still coming back with congestion despite all other therapies.

Conflicting Observational Studies

Some observational studies of digoxin have found that it is associated with decreased mortality, whereas others showed that it has a neutral effect, Madelaire said. According to the 2012 ESC guidelines, digoxin is the second-choice drug (after a beta-blocker) for patients with heart failure and reduced ejection fraction, and it is also the second-choice drug (after a calcium-channel blocker or beta-blocker) for patients with heart failure with preserved ejection fraction.

They aimed to assess the safety and effectiveness of digoxin in patients with heart failure and AF, based on data from Danish national registries. The study outcomes were risk of all-cause death and hospital readmission due to heart failure and/or AF during a 5-year follow-up.

They identified 70,263 patients who were discharged from the hospital with both heart failure and AF from 1996 to 2012. They excluded 48,598 patients who were not receiving a vitamin-K antagonist (eg, warfarin), were receiving antiarrhythmic therapy (eg, amiodarone), or did not survive until 30 days after discharge.

This left 21,665 patients: about half (10,989 patients) were treated with digoxin and the other half (10,676 patients) were not.

The patients who were treated with digoxin were younger than the other patients (mean age 74 vs 76, P<0.001), and they were less likely to have hypertension, cardiovascular disease, chronic renal failure, and diabetes; they were also less likely to receive concomitant ACE inhibitors or angiotensin-receptor blockers (ARBs), beta-blockers, spironolactone, or statins, but they were more likely to be receiving loop diuretics.

The researchers then matched 8078 digoxin-treated patients to 8078 control patients who were not taking digoxin, based on age, sex, year of inclusion in the study, comorbidities, CHA2DS2VASc score, medication, and heart-failure severity.

They classified the patients' heart-failure severity on the basis of the dosage of loop diuretics, from 1 (mild heart failure; <40-mg diuretics/day) to 4 (severe heart failure; >160-mg diuretics/day).

In the propensity-matched cohort, most patients were taking an ACE inhibitor or an ARB (69%) or a beta-blocker (64%) and fewer patients were taking spironolactone (27%).

In the 5-year follow-up, all-cause mortality was slightly lower in the digoxin group than in the control group: 5.4 deaths per 100 person-years (3342 deaths) vs 5.8 deaths per 100 person-years (3588 deaths).

However, the rate of hospital readmission was similar in the digoxin-treated patients vs the control patients: 7.8 readmissions per 100 person-years (4795 readmissions) vs 7.8 readmissions per 100 person-years (4769 readmissions), respectively.

Overall, patients who received digoxin had a lower risk of death during follow-up than control patients. The lower risk of death in digoxin-treated vs control patients was greater in patients with more severe heart failure.

Risk of Death During Follow-up, Digoxin-Treated Patients vs Control Patients

HF severity HR (95% CI)
Overall 0.89 (0.85–0.93)
Severity 1 (mild HF) 1.00 (0.87–1.16)
Severity 2 0.89 (0.83–0.95)
Severity 3 0.87 (0.79–0.95)
Severity 4 (severe HF) 0.82 (0.73–0.92)

There was no significant difference in the risk of readmission for heart failure or AF between patients who received digoxin vs control patients (HR 1.03, 95% CI 0.99–1.07). There was also no significant between-group difference for patients with less severe or more severe heart failure.


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