ESC 2020: Top 3 Studies

Prof Mamas Mamas


September 02, 2020

This transcript has been edited for clarity.

Hi, welcome to Medscape UK. My name is Mamas Mamas. I'm professor of cardiology based at Keele University, and today I'm going to present the top three trials presented at the European Society of Cardiology (ESC) just over the weekend. And I've chosen these trials because of their applicability and broad general interest.

Virtual Event

The ESC has been a very interesting event because of the COVID pandemic. It has been an online event. And this has really changed how, I suspect, we will all have meetings going forwards. First and foremost, the number of people registered for the meeting has tripled. The latest figures suggest that there have been over 115,000 registrations as opposed to 35,000 people last year. This has allowed people that would normally not have access to go to these meetings to attend the meeting. Mothers, people from the third world, and people that may not have the opportunity to take study leave.

I think this will change how we have meetings. And perhaps next year we will have a hybrid type of meeting.


A number of randomised control trials were presented at the meeting. And these are the three that I've chosen for discussion.

First and foremost, the EAST-AFNET 4 trial. Now this was an interesting trial testing whether there were superior outcomes associated with rate versus rhythm control in patients with AF.

Now, previous trials have been undertaken to investigate this. So for example, the AFFIRM trial was undertaken where patients were randomised to a rate versus rhythm control strategy. And this was run over 5 years.

Two thirds of patients remained in sinus rhythm at the end of 5 years in the rhythm control strategy, and a third of the patients ended up having a rate control strategy.

Most of these patients were investigated with sotalol and amiodarone, and there was no difference in hard clinical outcomes such as mortality and stroke.

Therefore, on the setting of this, the EAST-AFNET 4 trial was run. This was an open label randomised control trial of 2789 patients randomised to either a rhythm control strategy, which included drugs, mainly class I antiarrhythmic drugs, but also interestingly AF ablation versus a rate control strategy.

Fifty-percent of these patients had sinus rhythm at baseline. And these were patients that often had first episode of AF. We know that following instant AF, at a year there's a very high risk of cardiovascular event rates.

The primary outcome was cardiovascular death, stroke, hospitalisation from heart failure or acute coronary syndrome. And interestingly in this trial there was a 20% reduction in the primary endpoint associated with a rhythm control strategy. And certainly at the end of 2 years, 85% of patients in the rhythm control arm were still in sinus rhythm – it was only 60% in the rate control strategy.

So this is very interesting. I think, first and foremost, it shows that adopting an early and aggressive rhythm control strategy improves outcomes for patients. Certainly, even when you look at individual endpoints from the primary outcome, both stroke and cardiovascular death were reduced in this trial.

I think the second thing that's quite interesting is the importance and the growth of AF ablation.

At the start of the trial in the rhythm control strategy, 10% of patients had AF ablation. But by the end of the trial at 2 years, up to 1 in 5 patients in the rhythm control strategy ended up having an ablation.

I think this is going to change practice this trial and certainly in the new ESC AF guidelines there's very much a focus around ablation, particularly in patients that fail anti-arrhythmic therapy for attempts to maintain sinus rhythm.


The second trial that I want to talk about is the EMPEROR-Reduced trial. So we know that SGLT2 inhibitors have been shown to reduce heart failure hospitalisations in patients with cardiovascular disease. And also the DAPA-HF trial from last year showed a reduction associated with dapagliflozin of both heart failure hospitalisations and cardiovascular deaths.

The EMPEROR-Reduced trial focused on empagliflozin. This was a randomised control trial of 3730 patients with NYHA class II to IV heart failure with an ejection fraction of 40% or less.

This was a higher risk trial than the DAPA-HF trial. So for example, in patients with an ejection fraction between 30% and 40%, the authors required the patients to either have a heart failure hospitalisation in the past year, but also quite elevated brain natriuretic peptide levels.

The primary outcome of this trial was cardiovascular death, heart failure hospitalisation, and one of the secondary outcomes was a decline in eGFR.

The trial showed that in the empagliflozin arm of 10 mg once a day there was a 25% reduction in the primary endpoint. And this was mainly driven by a 30% reduction in heart failure hospitalisation, although the authors did not find any statistically significant change in mortality. They also reported a significant reduction in eGFR decline.

I think this is a very interesting trial. I think one of the things that many people discussed in this trial was why was there no reduction in cardiovascular mortality compared to the DAPA-HF trial. The main driver of the decline in composite endpoint in this trial was a reduction in heart failure hospitalisation.

Could it be that dapagliflozin and empagliflozin have different mechanisms of action, or are SGLT2 inhibitors known to have class effect?

Well, I think the differences in the two trials may be in part explained by the risk profiles of the population.

The EMPEROR-Reduced trial was a much higher risk population, but also much better managed.

So to give you an example, in the EMPEROR-Reduced trial, 20% of patients were on ARNIs, as opposed to only 10% in the DAPA-HF trial.

Secondly, in the EMPEROR-Reduced trial, over 30% of patients had ICD, 10% had CRT treatment, whereas in the DAPA-HF arm the number of patients receiving an ICD was only 10%.

And so it could be that with this better management it is much more difficult to see a reduction in mortality, and I think a reduction in heart failure hospitalisation is important.

Furthermore, I think the reduction in the decline of eGFR is incredibly important as well. We know in heart failure that a decline in renal function may often limit our ability to use many of the medications that we wish to use, and is associated with future risk of cardiovascular events.

So I think that both the DAPA-HF and the EMPEROR-Reduced trial have very much placed SGLT2 inhibitors in our armamentarium of treatments, and really raises the concept of quadruple therapy in patients with heart failure.

To my mind, the main challenges now are which therapies do we start? Do we start ARNIs instead of SGLT2s? Do we start SGLT2s in front of ARNIs? And how do these medications fit around things like beta-blockers, mineralocorticoid antagonists and so forth?

POPular TAVI[3]

The final trial that I'd like to talk around is the POPular TAVI trial. We know that patients that receive TAVI are often elderly and comorbid, and are at high risk of thromboembolic events, and there have been a number of studies looking at embolic protection devices to reduce the risk of stroke in this population group.

So the POPular TAVI trial looked at the optimal regime following a TAVI in terms of antithrombotic therapy, and patients, 665, were randomised to one of two arms, either dual antiplatelet therapy, that is, aspirin and clopidogrel for 3 months and aspirin thereafter, versus aspirin alone.

And they were randomised to this before the TAVI procedure. The mean age of the population recruited was 80, and this would be consistent with TAVI practice all over the world.

And the outcomes were major bleedings. Now these were either all major bleedings, so these could include minor, major or life-threatening bleeds, or non-procedural related bleeds. And these bleeds were defined by a number of different bleeding definitions. For example, BARC criteria, TIMI, BARC, and GUSTO.

And the secondary outcomes, one of them was ischaemic endpoint, so cardiovascular death, ischaemic stroke, or myocardial infarctions. And the outcomes at 12 months were all bleeds, 15% in the aspirin alone arm and 26.6% in the aspirin and clopidogrel arm.

Now, this was representing a 40% reduction in both the total bleeds, but also procedural bleeds. And this is important because in the paper, they also presented moderate to severe bleeds, life-threatening bleeds and so forth. And the single antiplatelet arm was associated with a reduction in not only minor bleeds, but much more significant bleeds as well. There was no significant difference in the outcome of cardiovascular death, ischaemic stroke, or MI between the two arms, the risk ratio of 0.98.

Why is this trial important? I think first and foremost, what it shows is that patients undergoing TAVI are high bleeding risk. I think that certainly in the dual antiplatelet arm, the vast majority of bleeds occurred within 30 days and looking at the Kaplan-Meier plots, over 20% of significant bleeds at this time point.

And this is probably related to the fact that many of these patients are anaemic, comorbid, and elderly, which increases their risk of major bleeding complications.

I think there are several other things that we need to consider.

It's a pity that this trial didn't have three arms. Certainly it is known that aspirin is associated with an increased risk of GI bleeds. And certainly a number of randomised controlled trials, particularly in the PCI space, have suggested that antiplatelet therapy, monotherapy such as ticagrelor, or prasugrel, or clopidogrel, are associated with better outcomes than dual antiplatelet therapy.

And so certainly what I would have liked to have seen was an arm with clopidogrel alone.

I think secondly, what we don't know is that there was no imaging endpoint into this trial. Therefore, we don't know whether there is an issue with subclinical thromboembolic events or thrombus on the valve. And certainly it's interesting to look in the supplements where echo data are presented and you can see that there was an increase of 5mm of mercury on echo parameters in the mean gradients across the valve, which may suggest that there is a possibility of thrombus developing on the valve.

I think there are many questions, particularly around whether aspirin is the best antiplatelet agent to use in this space, or whether a single agent such as a NOAC may be more appropriate. I think future trials should consider whether we use imaging. I think that will be very informative.


I think in summary these are three very important trials that I think will change practice in the heart failure, in the AF, and in the structural cardiology space.

I think from a takeaway perspective, I have found the ESC meeting to be fascinating in its digital format. I think it has opened it up to many people that would not otherwise be able to attend. And I think it's going to be very interesting to see how the ESC take this experience and build on it next year.

So thank you for joining me. And maybe in the comments, you can put your ideas about what were the most important trials to you, and whether the trials that I’ve discussed will change your practice. Thank you.

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