 Hi everybody. I'm David Berklin. I'm a cardiac electrophysiologist for Texas cardiac arrhythmia. I'd like to thank Dr. Coulter and the organizers for inviting me to speak today. I've been asked to talk about what the evidence tells us for timing of aphid ablations and this is actually a very relevant topic and a great time to discuss it as there's been a flurry of recent high-quality trials and meta-analysis aimed at answering just this question and so far the answer seems to be the sooner the better but we'll get into that in just a moment. I have no relevant disclosures and I'll start by asking why do we care about atrial fibrillation. So firstly it is the most common arrhythmia seen in clinical practice and it's becoming increasingly common as the general population ages with the prevalence projected to be over 12 million by 2030 just in the U.S. alone. Recent studies have shown that the estimated lifetime risk for developing aphid for individuals currently in their 40s and 50s is 22 to 26 percent. So there's about a 1 in 4 chance if you're currently in your 40s and 50s that you will develop aphid in your lifetime which is just staggering. And beyond the high prevalence aphid is expensive. Acute care of aphid patients accounts for about 1% of the overall health care cost with greater than $37 billion per annum and even 20 years ago the average aphid patient cost the health care system $7,000 per year which has no doubt gone up since that time. So we've established that aphid presents a huge problem. So why does early aggressive intervention make sense? Primarily because we've known for decades that aphid begets aphid and this is primarily due to electrical and structural remodeling that begins to occur very early in the course of atrial fibrillation, favoring maintenance of aphid over sinus rhythm. So studies have shown that within even 24 hours you can see the atrial refractory period decreases significantly which means that the atrium is able to be depolarized more rapidly which allows for more rapid activation and this favors re-entrant currents which are thought to be a major driving mechanism and sustaining mechanism of atrial fibrillation. And we also know that structural remodeling occurs quite quickly. Histological studies have shown that even by three to four months the normal relationship between atrial cardiomyocytes and the fibroblast scene at the top left is progressively distorted with the presence of myofibroblast, fibrous deposits in this disrupted extracellular matrix. And so the effect of this remodeling is that aphid becomes less about its triggering mechanism from these focal rapid firings within the pulmonary veins and more of a structural problem dependent on sustaining factors such as inflammation, fibrosis and oxidative stress which eventually leads aphid to permanently supplant sinus rhythm. And this is borne out well with the evidence with the 2014 decaf trial demonstrating that among patients with atrial fibrillation undergoing catheter ablation, increasing burden of atrial fibrosis estimated by cardiac MRI, a scar shown here by the green areas contrasted with the healthy blue areas, was independently associated with AF recurrence. And so you can see that AF recurrence is quite low in stage one atria, which are less than 10% total scar, about 18% over a year and a half after ablation versus in patients with very high scar burden in the stage four where the recurrence is close to 70% within about a year and a half post ablation. So taking a step back, what exactly are we doing in an aphid ablation? So a seminal study in 1998 by Dr. Hassegair demonstrated that aphid tends to arise from abnormal auto-maticity or rapid firing, which we mentioned earlier within the pulmonary veins, giving rise to the idea of pulmonary vein triggers. And he found that over 90% of aphid originated from these pulmonary vein triggers, which provides a meaningful target. And you can see these are your pulmonary veins looking here at the posterior left atrium. So the early attempts at aphid ablation involved directly mapping and targeting the pulmonary vein triggers themselves. So the ablation catheter was direct advanced into the pulmonary veins, and these multiple foci were identified and burned directly, regardless of how far into the veins they were found. And it was quickly discovered that veins don't take very well to burning at all and often respond to all that tissue architecture disruption by developing a severe stenosis, which you can see on CT in these areas here. And this is a devastating complication and causes refractory pulmonary hypertension with very, very few treatment options. So subsequently, we gradually moved away from burning inside the pulmonary veins to either burning or freezing around the ostea of the veins, which significantly improved the rate of pulmonary veins stenosis, but didn't entirely eliminate it. And so we've since moved to a wide area circumferential ablation or WACA, as it's referred to, outside of the pulmonary veins, which is our modern technique that leaves the venous tissue near and inside the ostea untouched. So getting back to the question at hand, let's take a look at one of the influential studies published from last year. So this is a trial at a Duke, headed by Dr. Pacini. It's a meta analysis of six large observational studies of about 5000 patients total that look specifically at ablation success rates relative to diagnosis to time of ablation. So in patients undergoing ablation within less than one year from time of diagnosis, there was a 27% relative risk reduction, AFib recurrence compared to those undergoing ablation greater than one year out from diagnosis. And you can see that that data here. So p value is less than 0.001. And the overall effect is 0.73. And this holds true as we look at the same outcomes in patients undergoing ablation within three years from the time of diagnosis versus greater than three years with a similar risk reduction rate. These results are highly suggested that there are early benefits to addressing AFib with ablation and that earlier rather than later tends to hold true at various points from initial diagnosis. And however this analysis, this is a compilation of observational studies and suffers from the same bias limitations you expect from these types of operational trials. So what are the randomized control trials show? So the test trial published just this year was an international multi center randomized control trial looking at patients with paroxysmal atrial fibrillation at high risk of progression. So that means the inclusion criteria looked specifically at patients who were greater than two years out from their initial diagnosis. And having already attempted at least one class one or class three anti rhythm drug. And the study was actually terminated early due to slow enrollment, but still managed to meet statistical significance with only 255 of the plan 322 patients completing three year follow up. So among the major takeaways from the trial was that patients treated with RF ablation were 10 times less likely to develop persistent atrial fibrillation than those treated with anti rhythmic drugs over a three year period. You can see how flap this ablation curve is relative to the anti rhythmic over those three years. And Dr. Andrade published another significant randomized control trial out of Canada also this year called early AF that looked at not just earlier ablations, but first line ablations. And about 300 patients with symptomatic paroxysmal nuance at AFib were assigned to either first line cryotherapy or anti rhythmic drug therapy for rhythm control. The primary endpoint was the first documented recurrence of any type of atrial arrhythmia, including AFib atrial flutter or atrial tachycardia. And this was a somewhat different trial because all patients underwent loop recorder implants at the time of procedure to establish continuous monitoring rather than the usual spot check EKG or event monitor. That's been done with so many of these prior ablation trials. And so that this is a much more strenuous outcome assessment, but but at the same time much more useful and descriptive. And so what was found was that first line ablation significantly improved upon the primary endpoint. About 60 percent of patients were free from any arrhythmia at one year versus only about 30% of patients on anti rhythmic drug therapy for a number needed to treat of about four. And in addition, first line ablation also reduced total AFib burden with a with a median burden of 0% as well as produce meaningful improvements in quality of life and symptoms. And it bears mentioning that that there were similar adverse event rates between the anti rhythmic drugs and cryo ablation in this trial. However, this was a relatively short trial. Follow up was only one year. So it really didn't allow for any evaluation of long term benefits such as progression of AFib to persistent or permanent or any kind of major cardiovascular adverse event. So this left this trial does leave a lot of important questions unanswered. And these results were were nearly duplicated with the very similar stop AF trial. This is also an international multicenter randomized control trial, looking at initial cryo ablation versus anti rhythmic drug also had 12 month follow up. There was a few less patients at about 200 versus the 300. And the primary efficacy endpoint was recurrence of asymptomatic arrhythmia between that three month blanking period that standard at the beginning of these trials and the one year follow up. So the results were very similar. There's a dramatic relative risk reduction with ablation compared to anti arithmetics. Absolute risk reduction about 30%. So again, a very, very low number needed to treat. And while these trials did show clear benefit and effective rhythm control, they're again not powered. Nor do they have long enough follow up to determine long term major major cardiovascular benefits. And so for more long term analysis, we look to the East AF net trial, which Dr. Zabe will go into more detail shortly. But in brief, the trial looked at a composite of death, stroke, heart failure and acute coronary syndrome hospitalization, and found that aggressive rhythm control, including ablation or anti rhythmic drug resulted in a 21% relative risk reduction to the usual approach of symptom based care, primarily centered upon rate control. So very few of the patients in the in the usual care group got an anti rhythmic drug. And the trial was actually stopped early at the third interim analysis doing due to the efficacy being met. A medium follow up was 5.1 years. Also very interestingly, these benefits appeared to apply equally to those patients who were asymptomatic at enrollment, and they made up about 30% of the trial. And this was looked at in in a post hoc analysis just published in the European heart journal about a month ago, specifically looking at symptomatic versus asymptomatic patients. And you can see that the data trends between the symptomatic and asymptomatic patients mirror each other with similar reduction in the composites mentioned of death, stroke, heart failure and ACS hospitalization. While of course neither separate group was powered to reach statistical significance, they did follow the same curve. And so so at a minimum, these results certainly warrant further investigation into the subset of asymptomatic patients. So what did the guidelines say about first line ablation upon AFib diagnosis? So even in 2017, before any of these studies were published guidelines, recognize populations where AF is deemed to be a reasonable first line therapy. So in particular, symptomatic patients with either paroxysmal or persistent AFib, or patients with atrial fibrillation and heart failure with reduced ejection fraction. And the guideline committee specifically commented that following the standard route of multiple anti rhythmic drug trials, cardioversion allows for further development of atrial fibrosis and a shift in complexity of management that favors substrate modification over the trigger targeting that Hossigar suggested all those years ago. So these these earlier studies are aimed at answering the question of what do we do with symptomatic symptomatic atrial fibrillation? But we're entering this new age of screening with highly dependable wearable cardiac monitors becoming more and more available. And these monitors are actually quite effective in detecting atrial fibrillation with single lead smartphone apps and continuous monitoring smartwatches demonstrating sensitivities and specificities in the high 90s. But what do we do with these patients when they're found? Does earlier the better mantra that we talked about earlier? Does this apply to patients with asymptomatic AFib? And it's a legitimate question to ask given that studies have shown that one in three new AFib cases are diagnosed after AFib hospitalizations in patients below the age of 75. And one in five patients suffer a stroke before AFib is detected. So clearly asymptomatic is not equal to benign. This tells us that too many undiagnosed AFib cases are slipping by routine care and that downstream consequences are not always preceded by symptoms. And so no one would argue the value of uncovering undiagnosed AFib. But with increased screening comes increased costs, increased burden to the patient anxiety, unnecessary testing, sometimes unnecessary procedures. There's increased burden of the clinician, the healthcare system in general. And, you know, the argument for broader screening is out of the scope of this presentation, but it will most certainly be a focus of studies in the near future. And finally, it's important to remember that while catheter regulation is the gold standard for rhythm management in atrial fibrillation, it's only one part of the total approach, which includes patient education, modifiable risk factor control, and a multidisciplinary approach, among other things. So in conclusion, evidence suggests that many patients stand to benefit from first line ablation therapy. And this is likely due to heading off atrial fibrosis, that inflammation that the toxic spiral of oxidative stress that shifts pathogenesis of atrial fibrillation from triggering mechanisms to sustaining ablation can actually decrease the cost of healthcare for patients with atrial fibrillation, updated guidelines support first line ablative therapy as a reasonable approach to either paroxysmal or persistent AFID patients with the appropriate choice benefit and risk. And these trials do not adequately inform us on how to manage the growing population of asymptomatic patients diagnosed. And this will no doubt be the focus of a variety of studies in the future. Thank you very much for your time.