 I'm Mehdi Razavi, one of the electrophysiologists at Texas Heart Institute, Baylor College of Medicine. I've been tasked with the subject of rhythm versus rate, has the tie changed since Affirm. Specifically, I've been tasked with kind of going back and revisiting the data that's been accumulated since the seminal study in 2002 that was released in the Affirm investigation. This was an NIH-sponsored study that looked at rhythm control strategy versus rate control. And it was a seminal paper because it essentially, at the time it appeared, it settled the discussion in the argument with regards to management of atrial fibrillation. It found that rhythm control strategy offers no survival advantage over rate control. As a matter of fact, there's a lower risk of adverse drug effects with the rate control strategy. And the study also found that anticoagulation should be continued in this group of high-risk patients. And based on that, this data that you see right now, you could see that there's really no obvious difference in terms of outcomes with these patients. And if anything, there was a trend that the rhythm control patients had a slightly higher risk of mortality. Keep in mind, however, that the statement to the right of the screen, no survival advantage with DC cardioversion and antiarrhythmic drugs. And if you note, something else is missing there, and that's catheter-based ablation. Just as the study was coming out, catheter ablation was starting to get its feet under itself and taking its first steps. So, at that point, the conclusions of the firm trial, which were stated as follows. Management of atrial fibrillation with rhythm control strategy offers no survival advantage over the rate control strategy. There are potential advantages lower risk of adverse drug effects with the rate control strategy. Anticoagulation should be continued. This conclusion was essentially an edict that was followed for many years in clinical practice. However, it really is time to revisit the conclusions of this study. As I noted a second ago, the biggest limitation of this study, it's simply that it's not relevant these days. The vast majority of patients are undergoing catheter ablation for rhythm management and not pharmacologic use. And we are going to kind of dive into the details of some of these studies to make the point that catheter ablation should not be precluded based on the firm study. So, why go beyond the firm trial? Rate control is different than rhythm control for all patients. And rhythm control strategies are continually improving. We also can't lose sight of special populations, those with coronary disease, those with heart failure, and those with valvular heart disease. These patients often tend to have the greatest benefit from other types of interventions, and perhaps catheter ablation is the same. So we're going to review some of the more recent data. We're going to go in chronological order, and at the end we will try to tease out our conclusions based on more recent clinical studies. So, couple of things. First of all, the endpoint, as we said with a firm, was one of mortality, and quality of life was not something that was necessarily looked at. However, if a retrospective analysis of that data, quality of life in patients with atrial fibrillation, found that actually in those same patients, the post-hoc analysis of a firm, more symptomatic heart failure occurred in the rate control group. And patients were less symptomatic in sinus rhythm. So in terms of quality of life, that was something that was clearly missing with a firm, that those patients who did manage to control their rhythm actually felt better than those who were in a rate control strategy. Shortly after the firm trial was released, another trial was published in the New England Journal of Medicine looking at catheter ablation for atrial fibrillation in those patients with congestive heart failure. And this really was the first study that gave us an inkling of how critical rhythm control is important, is in these group of patients. What you can see here is that in those patients who had rhythm control and heart failure, over time there's a progressive improvement in left ventricular ejection fraction, left ventricular fractional shortening, left ventricular endiastolic and end systolic volumes. And this was seen across all categories of patients in this trial, all the patients with heart failure. It did not matter whether or not they had ischemic heart disease or not. The benefit was real. You can see a dramatic improvement in LV fractional shortening, in a number of echocardiographic parameters, and again the ejection fraction itself. The next study is the CAMTAF trial, which is a randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation and heart failure. This study found that catheter ablation is effective in restoring sinus rhythm in selected patients with persistent AF and heart failure, and it can improve left ventricular function, functional capacity, and heart failure symptoms compared with rate control. In this slide we can see the Kapler-Meier curve showing the survival frame from atrial fibrillation or other atrial tachycardias after the last ablation procedure. At six months this number was 81% and at 12 months it was 73%. Here we can see a number of other parameters that we can see were significantly improved when you compare catheter ablation for atrial fibrillation versus medical management. We can see that the New York Heart Association class, BNP levels, LV ejection fraction, all these variables were significantly improved in the catheter ablation group versus those who underwent medical management. Based on these preliminary studies, the so-called CASL-AF study, catheter ablation for atrial fibrillation with heart failure, actually asked the hardest question, do patients benefit in terms of mortality from catheter ablation of atrial fibrillation if they have heart failure? This patient enrolled patients who had ischemic and non-ischemic cardiomyopathies, heart failure, and not necessarily symptoms related purely to the atrial fibrillation itself. And as you can see here, the patients across the board in terms of probability of survival, in terms of probability of hospitalization, and in terms of the combined probability of both ablation was superior to medical therapy and the difference was actually quite striking in some cases as low as P values of low as 0.004. This set up the stage for what was probably the largest EP clinical study in terms of catheter ablation in atrial fibrillation patients. It was an NIH funded spearheaded by Dr. Doug Packer at Mayo Clinic. This was an extremely important clinical trial and it showed the primary endpoint that catheter ablation is not superior to drug therapy for CV outcomes at five years among patients with new onset or untreated atrial fibrillation that required therapy. The study additionally found that there was a significant reduction in death or CV hospitalization with ablation and on as treated analysis, ablation demonstrated superior efficacy to drug therapy. In addition, recurrent AF and atrial fibrillation burden were lower with ablation compared with drug therapy alone. Catheter ablation was associated with a significant reduction in recurrent atrial fibrillation compared with drug therapy. Similarly, among patients with NYHA class 2-4 symptoms, most of whom have heart failure with preserved EF, there appeared to be a benefit in the primary endpoint and all caused mortality with ablation. No clear sex-based differences were noted in overall safety or efficacy in this large randomized trial. Further results from the cabana trial showed that in patients with atrial fibrillation enrolled in the cabana trial who had clinically diagnosed a stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. This was looking at the recurrences and quality of life and not focused on primary endpoint of mortality and hospitalizations. So they looked at a subgroup with heart failure and they found that there is a mortality benefit. So that's the take-home message here addressing this special group and we see this repeated across studies, even in cabana that overall was a negative study, that it seems that patients with heart failure really do response to this intervention quite nicely and quite effectively. You can see here that compared to drug therapy, the incidence of overall events was lower. Again, this is the cabana data in those patients who had catheter ablation. Similarly, overall, the event rate of all-cause mortality by intention to treat among cabana patients with heart failure, the incidence of mortality was lower with ablation than with drug therapy. Also, cumulative incidence of first recurrence of atrial fibrillation in the post-blanking period among cabana heart failure patients used the cabana ECG recording system. You can see that the freedom from recurrence was much higher in those patients who underwent catheter ablation as opposed to drug therapy. Finally, the question may be, well, okay, we have kind of settled that perhaps patients with heart failure should have catheter ablation, perhaps catheter ablation in and of itself. We've seen even in a unselected group of patients that cabana actually improved quality of life was associated not necessarily with improved mortality but a number of other end points such as even recurrent hospitalizations. So let's say that we are interested in approaching these patients using catheter ablation. When should we do this? Should we do this early on or should we wait as the atrial fibrillation progresses? So to answer this question, another study was performed and it looked at early rhythm control therapy in patients with atrial fibrillation. And in this case what was done is all 1,300 patients who were randomly assigned to early rhythm control received an anti-arhythmic drug or underwent atrial fibrillation ablation. This really replicated clinical practice patterns. Of the 1,400 patients, about 15% had a triggered visit to adapt rhythm control therapy. At 2 years, 900 of the 1,400 patients or about 2 thirds of them were still receiving rhythm control therapy. Usual care consisted of treatment with rate control therapy without rhythm control therapy throughout follow-up in the majority of patients assigned to this group. Initially about 95% of the 1,400 patients in this group had their condition managed without rhythm control therapy. At 2 years, about 85% were still not receiving rhythm control therapy or anti-arhythmic drugs. And you can see here that the cumulative incidence of the primary outcome of death or cardiovascular causes, there was a lower incidence in the early rhythm control population than there was that using the usual or standard care. This is another study. It's not really addressing the question of using catheter ablation in patients to improve mortality outcomes. But I think it's really important to take a step back and remember that a firm once again was not a trial really of rhythm control versus rate control. It was a trial of drug therapy versus rate control. And that's very important because what you can see is if you look at a number of larger studies taking ablation and comparing it to drug therapy, anti-arhythmic drugs, it frankly is not even close. The success of ablation as compared to anti-arhythmic drugs is essentially settled and there really is no debate these days that there is a significantly higher maintenance of normal sinus rhythm when undergoing catheter ablation as opposed to anti-arhythmic drugs. And again, this segues back to the original finding or the original population and the original firm study that really did not use catheter ablation. Again, I keep emphasizing this point because a firm is really not how clinical atrial fibrillation rhythm control is performed in 2021, not even close. Another study comparing anti-arhythmic drug therapy and radiofrequency catheter ablation in patients with atrial fibrillation reinforced the same message again. I'm not trying to beat a dead horse, but I'm trying to make sure that the message is getting through that what we're looking at is a comparison of catheter ablation and if you replace catheter ablation for drug therapy you should expect significant changes and differences in outcomes. And certainly we don't want to retrofit this data to affirm, but it's something that every clinician and every patient should keep in mind when making these very important decisions. Another study again looked at ablation versus amiodarone and I like to use this study because as we know amiodarone is by far the most powerful anti-arhythmic drug and even when using amiodarone there really it was not even close in terms of the incidence of recurrence of atrial fibrillation. The amiodarone group did far worse than the catheter ablation group for maintenance of normal rhythm. I'm going to make a slight change in direction right now to close off this talk because we've talked about catheter ablation of atrial fibrillation and Dr. Coulter tasked me with looking and revisiting a firm and that just doesn't mean that we have to consider catheter ablation of atrial fibrillation. You can actually perform rate control and one of the most effective ways of performing rate control is abenode ablation and pacing. Abenode ablation with permanent ventricular pacing currently is reasonable to control heart rate when pharmacological therapy is inadequate and rhythm control is not achievable. It's actually a class 2A indication in the guidelines. Abenode ablation provides highly effective control of ventricular rate in patients in whom pharmacological rate control has failed or the pharmacologic attempts have been associated with unacceptable side effects and or toxicities. Abenode ablation improves quality of life. It reduces mortality and in patients with reduced left ventricular function who may require biventricular pacing after abenode ablation their outcomes have also demonstrated to be excellent. As we said, a firm we're not trying to critique simply or be advocating for catheter ablation in all circumstances. There were other more subtle differences between a firm as it was done then and our clinical management these days. We now have a well-established chats to VASC scoring system to precisely, more precisely, risk stratify patients for the need for anticoagulation and very, very importantly, novel anticoagulants such as Dabigatran, Riveroxban, or Epixaban were simply never used in the affirm trial. So that's a very significant difference between current clinical practice and what was seen in affirm. So in conclusion, rate versus rhythm control strategy, rate control does not equal rhythm control for all and that question has to be significantly revisited. The affirm trial, its validity in current clinical practice is perhaps more limited and I would say confidently at least a bit more limited now than it was in 2002. Ablation is increasingly demonstrated to be safe and effective in selected patients especially in those patients with heart failure. Avynode, ablation and pacemaker is reasonable to control heart rate when pharmacological therapy is inadequate and rhythm control is not achievable and the novel oral anticoagulants are safe and effective. I would like to thank the organizers for providing this opportunity and thank you very much.