DIG Revisited: Digoxin Scrutinized Anew for Chronic Heart Failure

May 23, 2012

May 22, 2012 (Belgrade, Serbia) — Subgroup data from a 15-year-old trial, publicly released for the first time, suggests an old drug has potential for broader use in chronic heart failure even in the modern age of multidrug neurohormonal blockade, according to a presentation here at the Heart Failure Congress 2012 sessions of the European Society of Cardiology Heart Failure Association [1].

More than half of the 6800 patients with systolic HF randomized in the placebo-controlled Digitalis Investigation Group (DIG) trial [2] fell into three high-risk subgroups, and in all three, HF-related mortality or hospitalization fell off significantly over two years for patients receiving digoxin. The composite of all-cause mortality or hospitalization also declined significantly but less sharply.

But mortality didn't figure much in either of the two benefits, which were driven primarily by fewer hospitalizations with digoxin, observed Dr Mihai Gheorghiade (Northwestern University Feinberg School of Medicine, Chicago, IL) when presenting the prespecified DIG high-risk subgroup analysis. That's consistent with the overall trial's negative outcome for its primary end point, all-cause mortality on its own.

Still, when HF-specific events are figured into the outcomes, he emphasized, the risk reductions were "robust" for all three high-risk subgroups: those in NYHA class 3 or 4, with an LVEF <25%, or with a cardiothoracic ratio (CTR) >55.

The FDA considered the high-risk-subgroup data when it approved digoxin for heart failure in 1998, according to Gheorghiade, yet the findings have never before been published or presented at a meeting. But he cautions against generalizing them to contemporary practice, as all patients in DIG were on ACE inhibitors and diuretics but few, if any, were on beta blockers or aldosterone antagonists.

Still, he said, "Based on this data, and this is consistent with the guidelines, I think digoxin therapy should be considered in patients who continue to have signs and symptoms in spite of available therapies. But this is not happening. There are many patients who continue to have signs and symptoms at my own institution, and digoxin is not even considered."

Maybe we should also have it in our minds for those intolerant of beta blockade.

As the featured discussant for Gheorghiade's presentation, Prof Theresa A McDonagh (King's College Hospital, London, UK) said the subanalysis "should have us revisit our thoughts about digoxin in heart failure." The drug has fallen out of favor in HF since DIG with the broadened use of neurohormonal blocking agents, but also "maybe because DIG was performed in the era of the all-cause-mortality trials and seen as a failed trial because it missed its primary end point. Since then, digoxin is no longer seen as a first-line therapy and has been relegated from the premier league of drugs for reduced-ejection-fraction heart failure."

The guidelines still say it should be considered for low-LVEF patients with heart failure "who have deteriorating symptoms despite conventional contemporary heart-failure treatment." And, she added, "maybe we should also have it in our minds for those intolerant of beta blockade."

DIG Prespecified High-Risk-Subgroup Analysis: Hazard Ratios (95% CI), P, for Composite End Points That Include Hospitalization

End points NYHA 3-4, n=2223 LVEF<25%, n=2256 CTR >55%, n=2345 Any of the 3 high-risk features, n=4367
All-cause mortality or hospitalization 0.88 (0.80–0.97); p=0.012 0.84 (0.76–0.93); p=0.001 0.85 (0.77–0.94); p=0.002 0.87 (0.81–0.94); p<0.001
Heart-failure-related mortality or hospitalization 0.65 (0.57–0.75); p<0.001 0.61 (0.53–0.71); p<0.001 0.65 (0.57–0.75); p<0.001 0.66 (0.59–0.73); p<0.001

CTR=cardiothoracic ratio

According to Gheorghiade, studies should explore whether digoxin should also have a role for patients hospitalized for heart failure, "where the event rate is unacceptably high in spite of available therapy."

Dr Piotr Ponikowski (Medical University, Clinical Military Hospital, Wroclaw, Poland) told heartwire that he agrees that DIG was performed in a previous era and "today we have a completely different population, because most of our patients are on neuroendocrine blockade." But the "reassuring" and "promising" DIG subgroup analysis should help revitalize interest in the drug for heart failure, he said. "I strongly believe we may need to revisit the data again in the contemporary population."

Often forgotten, according to Ponikowsky, is that digoxin lowers heart rate and so "is not just an inotrope." But it also has well recognized adverse side effects. "Obviously in ivabradine [Procoralan, Servier], which also lowers the heart rate, we have something powerful in our hands. The data are very clear that [it leads to] reductions in hospitalization and in heart-failure death, and the safety profile is also very encouraging--which gives us a little bit less enthusiasm for digoxin."

Gheorghiade discloses consulting for Bayer Healthcare, Abbott, Astellas, AstraZeneca, CorThera, Cytokinetics, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Novartis, Otsuka, Pericor Therapeutics, Protein Design, Sanofi, Sigma Tau, Solvay, and Takada. McDonagh had no disclosures. Ponikowsky discloses consulting for Abbott Vascular.