Kevin Damman: I'm Kevin Damman. I'm a heart failure cardiologist from the UMCG Groningen in the Netherlands.

Interviewer: Can you provide some background on digitalis glycosides?

Kevin Damman: Yeah. So, digitalis glycosides such as digoxin and digitoxin have been around for centuries actually. So, they've been used in cardiovascular disease specifically in heart failure and atrial fibrillation. And already 20 years ago, even 30 years ago, there was a large trial called DIG which didn't meet its primary endpoint. So, there was no reduction in all-cause mortality. There was a signal for improvement in heart failure hospitalization. But that was not enough to get this compound used often as foundational drugs as we use them today. And thereafter many other drugs were introduced and digoxin and digitoxin were not first-line therapies anymore. And now we have two trials. Last year DIGIT-HF was published showing that with that digitalis glycoside there was an improvement in the primary outcome. And yesterday we heard from my colleague the DECISION trial, a Dutch trial of 1,000 patients, where we investigated low-dose digoxin that didn't meet its primary endpoint of cardiovascular death or recurrent worsening heart failure events. So that's where we are today. So we have trials from 30 years ago with a neutral effect on the primary endpoint. One trial with a positive effect last year and now we also have a neutral or inconclusive trial yesterday with low-dose digoxin.

Interviewer: What was the rationale for conducting a meta-analysis?

Kevin Damman: Yeah. So this is also the reason to conduct a meta-analysis. If you have at least results that are not in line, you will try to pool them and see if you have more power with more studies with more patients if you can still see the same signal or a different signal. To remind everybody, DIGIT-HF and DECISION were small trials, relatively small, 1,200 patients. So that's also a reason to see if we can actually now in the contemporary heart failure patients with foundational drugs as we're using today if there still is a signal for low-dose digitalis glycosides as additive medical therapy in heart failure.

Interviewer: Can you describe the meta-analysis methodology?

Kevin Damman: Yeah. So this study-level meta-analysis consists of the three trials we just discussed. So DIG, DIGIT-HF and DECISION—overall 9,000 patients. And when we pooled this and looked at the endpoint that we've chosen, we chose time to cardiovascular death or first heart failure worsening heart failure event, there was a 15% relative risk reduction across all studies. So that means that on top of what we now use as foundational medical therapy, digitoxin and digoxin in low dose had a 15% relative risk reduction on top of that. So I think that just speaks for the efficacy of this even in the context of what we're using currently.

Interviewer: What were the key findings?

Kevin Damman: So yeah, the key findings were that there was a risk reduction when pooling all studies together—so 15% relative risk reduction for the primary outcome of cardiovascular death or time to first worsening heart failure event. But we also saw a reduction in first heart failure event—so 25% relative risk reduction. But low-dose digoxin or low-dose digitoxin did not result in a reduced risk of all-cause or cardiovascular death.

Interviewer: What are the implications for clinical guidelines?

Kevin Damman: So the current guidelines will be updated in September. I'm not sure if this data will make it into the new guidelines, but if we would draft guidelines today with all these data together with also with the new level of evidence that we introduced by the ESC, I think this strongly suggests that we should use these drugs as the fifth pillar in heart failure medical therapy. These drugs are very cost-effective. They cost nothing. We've been used for hundreds of years. They're safe in a low dose. But I think this should be considered as additional medical therapy in patients with heart failure with mildly reduced and reduced ejection fraction.

Interviewer: What's your perspective on future research and clinical use?

Kevin Damman: Yeah, I would hope that there would be even more trials confirming what we showed in the meta-analysis. I think that's unfortunately not going to happen. So we have to do with the data we have today and I think again that adding digoxin or low-dose digitoxin on top of the drugs that we're currently using is safe. It seems to have an effect on heart failure hospitalization and worsening heart failure events. So I would say why not just use it? I think this will improve the outcomes of our patients.