Hi, my name is John Bacini, I'm a Cardiac Clinical Physiologist at Duke, and I'm very pleased to be with you today to discuss practical approaches to the treatment of early atrial fibrillation with anti-rhythmic drug therapy. Shown here are my disclosures. Please note that I have relationships with organizations that manufacture rhythm control drugs and devices. I thought we could start with a case. Consider the case of a 72-year-old gentleman with hypertension who had a pulmonary embolus two months ago. He comes into your office for heart rhythm follow-up and has persistent atrial fibrillation that was initially discovered at the time of his pulmonary embolism. You evaluate this patient, and you discover that he's had dyspnea with yard work since recovering from his PE acutely. He is on apixaban. He is taking Toprol XL for rate control. He has a normal thyroid profile. He does not have an elevated brain natriuretic peptide. His renal function is preserved, and an echocardiogram reveals normal ventricular function. His right ventricular systolic pressure is not elevated, and his left atrial size is just above the upper limit of normal by the atrial volume index. So how should we approach this patient who has a diagnosis of atrial fibrillation within two months? I would argue that this patient would benefit from an attempt at rhythm control, and I think you've already heard some evidence earlier in the program regarding clinical trials that can speak to this and the recommendations from the guidelines. We know that atrial fibrillation is a progressive disease, and the general concept is that if we can interrupt it and restore sinus rhythm, we can improve outcomes. But who benefits the most from early rhythm control? Well, if we revisit the EAST clinical trial that randomized patients to usual care or early rhythm control, we can begin to get an idea to the answer of who benefits the most. It's important to point out that everyone at some point in time is within one year of their diagnosis of atrial fibrillation. So in one sense, all patients can be considered for early rhythm control. But reflecting back on the EAST trial, you can see that the average age was 70 years. Almost half of the participants were women. There was a good heterogeneous representation of different forms of AFib, including both paroxysmal and persistent forms. About 30% had heart failure, and the average TRAS-Vasc score was about 3.5. I would argue that this patient profile looks like many of the patients we encounter with a diagnosis of atrial fibrillation in our clinics. However, there is a range of therapeutic urgency for the application of early rhythm control therapy. Patients who have no symptoms or have brief and infrequent symptoms have a lower need or urgency than patients who have significant symptoms like dyspnea, those that require cardioversion, those that have required ER visits or hospitalization, and those patients who have more manifest complications of atrial fibrillation, including the development of heart failure, left ventricular dysfunction, high TRAS-Vasc scores and comorbidity profiles, and those experiencing AFib progression. It's also important when we think about applying early rhythm control to maintain a very high suspicion for the presence of heart failure with a preserved ejection fraction. This is a study called the STAL-AF HEF-PEF study in which patients who presented with dyspnea and atrial fibrillation underwent a very thorough evaluation. And the most important aspect of this study is that 65% of patients who presented with atrial fibrillation and dyspnea had objective evidence of heart failure with a preserved ejection fraction. Thus, we need to maintain a very high suspicion for the presence of HEF-PEF when we encounter these patients. Of course, rhythm control can't fix anything. Severe cases of structural heart disease with an underlying structural deformity like severe mitral regurgitation, core pulmonality, severe pulmonary hypertension that is often accompanied by other disorders, and massive left atrial enlargement are not likely to allow a high degree of success with early rhythm control. And so one should also keep this in mind when selecting patients for an early rhythm control strategy. Another question that comes up in the practical application of early rhythm control is, which drug should I select for a patient for early rhythm control? Again, you have reviewed the guidelines in a previous lecture. But largely, the selection of an anti-rhythmic drug or any rhythm control strategy is predicated on the patient's comorbidities and the presence or absence of structural heart disease. So we can see here, patients who have no structural heart disease are eligible for many anti-rhythmic drugs, including class Ic agents, class III agents, and multichannel blockers, whereas those with structural heart disease like heart failure are eligible for very few agents. And in the case of Hef-REF, patients are only eligible for amiodarone and dofetilide, according to the current ACC, AHA, HRS guidelines. If we review the guidelines for the European Society of Cardiology published in 2020, we see the options are largely similar. Of course, dofetilide is not available in the EU. Their guidelines also allow for the use of dronetarone with Hef-PEF. And there are considerable data for that, again, as likely reviewed in our previous lecture looking at the randomized evidence for application of rhythm control. However, the two guidelines largely have more in common than they do not. One important thing to remember when we're considering early rhythm control is that the guidelines counsel against using a medication like amiodarone that has significant potential for adverse effects as a first-line rhythm control agent. Despite this clear counsel from the guidelines, when we look in clinical practice, we see that the vast majority of patients treated with amiodarone do have other options available for anti-rhythmic drug therapy. It's important to avoid the use of amiodarone in these patients, as it's associated with adverse outcomes, including increased risk of all-cause death, as well as increased risks of cardiovascular events and non-cardiovascular toxicities, including things like lung disease and other toxicities. It's important to remember when prescribing anti-rhythmic drugs the important contraindications to certain drugs and their monitoring requirements. So for example, in the case of flecainide and propafenone, patients should have no structural heart disease or coronary artery disease. They require electrocardiograph monitoring for PR and QRS prolongation, and these drugs should be discontinued if patients have significant PR or QRS prolongation, especially the development of a new bundle branch block. They also require adjunctive avenodal blocking therapy to prevent things like one-to-one conduction of atrial flutter. Similarly, class 3 medications can be used, and important things to keep in mind with class 3 anti-rhythmic drugs that block the potassium channels are that they should be avoided in patients with CKD, at least moderate to severe CKD, as they are metabolized renally, and even if a patient is eligible for a dose reduction, these patients often experience health care events that result in fluctuation of their renal function, like if they develop a bout of influenza and develop pre-renal isatemia. They require inpatient loading, and they require frequent metabolic monitoring, including basic metabolic panel testing and magnesium determination every three months. They also require both patients on these medications and their health care providers to be extremely vigilant for drug-drug interactions, and before prescribing these medications, it's critically important to educate patients about these potential drug-drug interactions, and to provide them, in many instances, a card that they can show to their health care provider. Now I just want to take one step back. It is not that amiodarone is never appropriate. However, we want to avoid it as a first-line agent. There are some patients where amiodarone is highly appropriate, especially patients who present with tachycardia-induced cardiomyopathy, or patients who have comorbidities that preclude the use of any other antiarrhythmic medication. Another important option is dronetarone. It has been shown in randomized clinical trials to reduce cardiovascular hospitalization in patients with atrial fibrillation, and with respect to early atrial fibrillation, there are post-hoc analyses from clinical trials that suggest that it may form particularly well in persons with early atrial fibrillation. However, as mentioned previously, it should be avoided in patients with heart failure reduced ejection fraction, or those patients with advanced heart failure with class III or IV symptoms. It should also be avoided in persons with permanent AF, where it's been associated with an excess of adverse events and increased death. Another important question that often comes up when considering these patients is that, does delaying ablation have negative implications for rhythm control? This question comes up because when we look at clinical trials like early AF, which randomized patients for initial treatment of atrial fibrillation to catheter ablation or anarrhythmic drug therapy, we see superior maintenance of sinus rhythm in patients who undergo ablation. Similarly, there have been analyses that demonstrate maintenance of sinus rhythm is better when patients are treated more proximal to their diagnosis, with a time from diagnosis to ablation of one year or less relative from longer periods of time from diagnosis to ablation. These are data from a meta-analysis performed by Dr. Derek Chu at the University of Calgary. However, there is a very recent randomized trial that directly addresses this issue and randomized 100 symptomatic patients with atrial fibrillation to delayed ablation or early ablation. And what the investigators saw is that if the patients with delayed ablation received high-quality rhythm control, largely with anarrhythmic drug therapy and frequent monitoring, there was no difference in freedom from atrial fibrillation and follow-up. Moreover, there was no difference in AFib burden in those treated with early ablation or delayed ablation. It's also important to remember that in the EAST trial, where there was a benefit and reduction of cardiovascular events at five years, the vast majority of the patients shown in the far left column were treated with anarrhythmic drug therapy and not catheter ablation. So the message is that it is important to implement early rhythm control to improve outcomes. But as long as patients are receiving high-quality rhythm control, we do not have to worry about significantly reduced risks of being able to maintain sinus rhythm. So in conclusion, early rhythm control improves outcomes in persons with atrial fibrillation. The vast majority of patients should be offered early rhythm control, although there are degrees of urgency. Anarrhythmic drug therapy should be guideline-directed, highly personalized to each patient, and based upon comorbidity profiles and optimal concerns for pharmacologic safety. There are no adverse effects with delayed ablation and randomized trials if, and this is a big if, if patients receive high-quality rhythm control. I hope these considerations have been helpful to you as you contemplate who may benefit the most from early rhythm control in your practice. I'd like to thank you and the American College of Cardiology for your time and attention.

John Bacini

Cardiac Clinical Physiologist

atrial fibrillation

anti-rhythmic drug therapy

rhythm control