Hi, my name is Paulus Gerjof and today I'm going to talk about recent clinical data on rhythm control strategies and implications for patient care. These are my disclosures. Now, the starting point of the new data that I want to talk to you about was summarized in the design paper of the EAST-AFN 412 published in 2013. And it shows you, this busy table shows you the event rates in rate versus rhythm and rhythm control and anticoagulation trials in atrial fibrillation. And you can appreciate two things. One, even on optimal anticoagulation rate control and background therapy of compromising conditions, there is still a measurable rate of stroke and cardiovascular death and also heart failure hospitalizations in patients with atrial fibrillation. And two, and I've marked the Athena data in green, there is one signal that suggests that rhythm control therapy using antiarrhythmic drugs may reduce that rate. But there are others, and that includes AFCHF and DEFIRM and RACE and other older trials that suggest that choosing a rhythm control therapy strategy for all relying only on antiarrhythmic drugs may not include these outcomes. Now, the early rhythm control for stroke prevention EAST-AFN 412 tested whether a modern rhythm control therapy that integrates antiarrhythmic drugs and AF fibrillation can reduce these outcomes. And it was a very simple trial. It took consecutive patients in 135 sites that had recently diagnosed atrial fibrillation, less than a year of atrial fibrillation duration, and at least two of the Chatsvarsk risk factors, and randomized them to early rhythm control, the therapy strategy that applied rhythm control to everyone after enrollment of randomization, or to usual care, the treatment strategy that randomized patients to usual care consisting of an initial trial of rate control therapy and the switch to rhythm control only when they were still symptomatic. You've probably seen the headline outcome, a strategy of early rhythm control therapy in all patients reduces cardiovascular outcomes over a mean follow-up of five years by 21%. So every fifth primary outcome event was prevented. The primary outcome was a composite of cardiovascular death, stroke, or unplanned hospitalization for heart failure or acute chronic symptom. Now, how was that strategy delivered? And this is shown in these psyche plots that show you the delivered therapy at randomization at 12 months and at two years. And on the left, at randomization, you see that almost everyone randomized to early rhythm control, on the left in the slide, received rhythm control therapy, mainly antiarrhythmic drugs, approximately 8% to 10% AF fibrillations. At the two-year time point, every fourth patient still in follow-up at that time point had received AF fibrillation. The majority were still on antiarrhythmic drugs, and quite a few were not on rhythm control therapy. So there were some patients who were considered, if you wish, rhythm control therapy. Whilst usual care, on the right, is dominated by no rhythm control therapy in gray, with a few patients needing antiarrhythmic drugs and a few needing AF fibrillation. Now this main finding, systematic early rhythm control therapy as a strategy prevents every fifth outcome, was consistent in quite a few subgroup studies, so patients with heart failure and patients with and without symptoms, so including in asymptomatic patients, about a third of the patients in East AF report, independent of how rhythm control was delivered, at least in the trial, independent of whether patients were enrolled with first diagnosed paroxysmal or persistent atrial fibrillation, and independent of whether they had a prior stroke or not. It also worked in men and women, and it worked across the spectrum of genetic AF risks. And a recent analysis suggests that early rhythm control was also cost effective and accepted cost thresholds per event prevented, if you take real observed data and the German healthcare system as a standard system. Now these observations led to a proposal, and this is from a consensus paper organized by the German AFNet and the European Heart Rhythm Association, that the AVC approach to managing atrial fibrillation, anticoagulation, better rhythm management, and cardiovascular risk factor management should be better rhythm management for the B, where rhythm control therapy would probably be the default for most patients. Now, one analysis in the yeast trial suggested an interaction with the treatment effect. And this was when we split the patients randomized in the yeast trial by their co-morbidity burden. And interestingly, I mean, and probably a bit counterintuitive and a bit different to our rhythm control practice in the past, the patients who were older with multiple co-morbidity, quantified by a CHATS-VASC score of four or more, had a clear reduction in primary outcomes when they were randomized to early rhythm control, whilst the patients with a CHATS-VASC score of two or three had less benefit. And that was a significant treatment interaction. So one would think that it is particularly the elderly and the patients with multiple co-morbidities and recently diagnosed atrial fibrillation that would be eligible for early rhythm control to improve outcomes. Now we and others also analyzed large datasets in these examples, the UK Biobank and a large U.S. American healthcare dataset, and asked two things. One, how many patients with newly diagnosed atrial fibrillation are eligible for early rhythm control? And it turns out that the vast majority, between two-thirds and 80% of patients with newly diagnosed atrial fibrillation in the UK are eligible for early rhythm control based on the enrollment criteria of the EAST-AFD score. And also that this outcome-reducing effect can be replicated in these observational datasets. Now obviously comparing efficacy of treatments is not a strength of observational datasets, but confirming the safety is. One of the key findings of EAST-AFNF4 in the trial and in these large dataset analyses is that modern rhythm control therapy as delivered in EAST or as delivered in these datasets is safe and that our historic fear of proarrhythmia, bradycardia, or tachycardia is related to very rare events and can be avoided in most patients. We also did a complex mediator analysis trying to identify the clinical factors that were associated with improved outcomes in the EAST-AFNF4 trial. And to do this, we looked at all the parameters that were measured in person at the one-year follow-up visit in EAST-AFNF4 and checked for all parameters that were different between patients randomized to early rhythm control and patients randomized to usual care. Of all the factors that were different, we looked how much of the outcome-reducing effect could be attributed to that factor. This was a complex analysis, took over a year and multiple statisticians to calculate it. But in the end, we found one dominating factor, and that was the presence of sinus rhythm at 12 months. So attaining sinus rhythm through early rhythm control therapy mediated the effect of early rhythm control in the four years of follow-up ASTR1.1 visit. The presence of sinus rhythm at 12 months was a better and stronger mediator of early rhythm control than anything else, including recurrent atrial fibrillation. And I think that gives you a bit of a breathing space that not every recurrence of atrial fibrillation means that rhythm control therapy as a strategy has failed, but that in the long term, we want to achieve sinus rhythm. So that in summary, early rhythm control therapy is one of the components of atrial fibrillation management that can be used to improve cardiovascular health to prevent outcomes. Early rhythm control therapy reduces cardiovascular outcomes in patients with recently diagnosed atrial fibrillation when added to anticoagulation and therapy of complementary conditions. Early rhythm control, as tested in the East AFL-4 trial, relied mainly on antiarrhythmic drugs. The result is consistent across clinical subgroups and across the range of genetic diagnostics. Most patients with recently diagnosed atrial fibrillation, for example, in the UK Biobank population-based sample, are eligible for early rhythm control. Attaining sinus rhythm is the main mediator of the effect of early rhythm control, and AF fibrillation trials in older patients with multiple comorbidities are needed to substantiate our interaction analysis, suggesting that rhythm control therapy is particularly effective in patients with multiple comorbidities. I hope this was interesting to you, and I wish you a good day.

rhythm control strategies

atrial fibrillation

early rhythm control therapy

antiarrhythmic drugs

cardiovascular events