Benefits of an Expedited Intravenous Sotalol Loading Protocol: Information on the PEAKS Registry

Interview With Benjamin A Steinberg, MD, MHS, FHRS

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EP LAB DIGEST. 2024;24(9):20-21.

In this interview, EP Lab Digest talks with Benjamin A Steinberg, MD, MHS, FHRS, about findings and implications of the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry.

Can you provide an overview of the objectives of the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry?

Absolutely, thank you for the opportunity to talk about this important study. The primary objectives of the PEAKS Registry¹ were to, in an observational perspective fashion, really understand the feasibility and safety of an expedited intravenous (IV) approach to loading sotalol for use in atrial arrhythmias. The primary objective was around safety and feasibility. We had secondary objectives in terms of looking at the utility of mobile electrocardiogram (ECG) to monitor QT in those patients and also establish a pharmacokinetic-pharmacodynamic (PKPD) profile for this type of loading among patients with atrial arrhythmias.

What was the rationale behind exploring expedited loading with IV sotalol?

As you know, sotalol has been around for a long time for the treatment of both atrial and ventricular arrhythmias, primarily labeled for atrial arrhythmias. The motivation here was that more recently, in the last couple of years, the labeling was changed and there was US Food and Drug Administration (FDA) labeling approval for IV infusion for a loading protocol. That approval was granted under kind of a novel FDA pathway using simulated data and calculations due to the high familiarity with oral sotalol in the kinetics of that drug. So, despite being approved, there were actually no in vivo patient data, in other words, patients with atrial arrhythmias who had undergone this expedited loading prior to approval. So, that was the primary motivation to provide clinicians with patient-based clinical real-world practice data for the use of expedited IV loading of sotalol in patients with atrial arrhythmias. 

How was patient selection conducted for the PEAKS Registry? Were there any specific inclusion/exclusion criteria for participants in this registry?

We wanted to study patients who were routinely treated with sotalol for atrial arrhythmias, and we wanted a rather broad but reasonable inclusion of patients. As you know, there is wide diversity in the use of antiarrhythmics. So, the inclusion criteria for the PEAKS study were really geared towards those objectives. That’s to say that patients that were eligible for class 3 antiarrhythmic drugs by atrial fibrillation (AF) guidelines were included. So, we excluded patients whose renal function would not support the drug, who had prior or known QT prolongation with prior class 3 antiarrhythmics, or had baseline QT abnormalities, as well as those with any other concomitant diseases, specifically severe left ventricular hypertrophy, that might have changed their risk profile for sotalol. So those were the primary inclusion criteria aligned with the objectives of the registry. 

What were the primary endpoints assessed in this study? 

So again, aligned with the objectives, our primary endpoints were based mostly around safety and feasibility. In other words, the effectiveness of sotalol has been previously studied and established, and we did not necessarily expect there to be differences, nor was that a primary objective. So, the endpoints were principally around safety, in other words, if there were any significant episodes of bradycardia or hypotension or ventricular arrhythmia among patients undergoing this expedited IV load in contrast with historical oral loading. 

Could you describe the protocol used for expedited loading with IV sotalol?

As an observational registry, we geared the protocol towards adherence to the FDA labeling. However, that was not mandated. Sites could pursue the loading paradigm however they saw fit. As it happened in the registry, the majority of patients who were enrolled and underwent IV loading for atrial arrhythmias was consistent with FDA labeling. What that entails is an hour-long fusion dose of IV sotalol with QT monitoring, followed by an oral dose an hour or so later, and then followed by a second oral dose 12 hours later prior to discharge. So, the majority of patients had an IV dose and 2 oral doses prior to discharge, consistent with the FDA labeling. However, there were some sites that were real early adopters and had additional experience. So, there are some patients that were discharged even earlier prior to the second oral dose, although it should be noted that was a minority of patients in the study, and it should certainly be noticed that that is not currently the FDA labeling for its use. 

What were the key findings regarding the safety of IV sotalol loading?

So, we enrolled nearly 170 patients at about 10 to 12 sites, and we found that, first of all, even among sites that had not done this much, it was relatively easily adopted, and they did realize the expected improvement in length of stay. In other words, patients truly did go home sooner, which was part of our secondary objectives, but I think it is an important finding that even among sites that did not have much experience with the protocol how that was feasible. Importantly, we found a relatively very low rate of adverse events associated with IV sotalol, a handful of patients with either bradycardia or hypotension associated with the infusion or the early load, and there were no in-hospital ventricular arrhythmia events warranting clinical action. We found overall that the safety and feasibility of doing this in a clinical population across diverse sites, which included academic centers as well as private centers, was favorable. 

How do the results of the PEAKS Registry compare with previous studies on intravenous sotalol administration?

Great question. I think it is important to take this question in the context of the field, which is that the reason we embarked on this study is that there were relatively few data on the elective or urgent use of IV sotalol in adults for atrial arrhythmias. The one exception that should be noted is the DASH-AF study, which was published last fall. That was a study looking at what I would say even further expedited loading of sotalol, essentially off-label discharge prior to the second oral dose. That study suggested that that approach also was safe and feasible, although, again, it should be noted that that is not currently the FDA labeling. Taken together, both DASH-AF and the PEAKS registry, I think demonstrate robust data for the safety and feasibility of the use of IV sotalol for elective loading for atrial arrhythmias, at least in the patient population studied, although, again, it is important to understand differences in the study’s protocol and approach. 

What are the potential clinical implications of expedited loading with IV sotalol?

Yes, this is of great interest, and obviously it came to heightened priority in the setting of the pandemic, which is to say the benefit is health care utilization and resources. Essentially, instead of patients being in the hospital for 5 to 6 oral doses, essentially 3 days for sotalol loading, using an expedited IV approach, we can get that down to 24 hours or less. It should be noted that there are clinicians and centers out there that load sotalol as outpatients and do not hospitalize many patients. But there remain many centers, particularly ours and others, where loading of class 3 antiarrhythmics still occurs in inpatients, particularly in higher risk patients. I think we demonstrated that, at least in this type of population, it can be done safely and you can realize the reduction and length of stay quite easily. There are other data published by our group and others demonstrating cost benefit or cost equivalence between a shortened IV load and a more prolonged oral load. It is important also to understand that those types of analyses do not take into account the benefit of the opportunity for other patients to use the bed that is freed up with a shorter stay. So, there likely is cost benefit overall for a shorter load.

What are some areas that future research should focus on, based on the findings of the PEAKS Registry?

There is always more to study. So, we published the primary results demonstrating the clinical outcomes and the feasibility of the load. We expect to publish results of the PKPD study, giving a look into how the drug acts in the bodies of patients with atrial arrhythmias, which has not yet been looked at. We are also going to do an analysis on use of the mobile ECG to measure QT among these patients in the safety and utility or lack thereof in terms of assessing safety among patients getting sotalol. I think there are additional interests in looking at different doses of sotalol and the use of IV loading therein. Then, as I alluded to earlier, when combined with the DASH-AF study, I think there is intense interest into whether or not the hospitalization load can be shortened even further beyond the current FDA labelling. So, that is an area of intense interest, particularly as clinicians and hospitals become more and more comfortable with the use of IV sotalol. 

How do the results of this registry contribute to our understanding of antiarrhythmic therapy?

This is a great question and a great challenge in our field. As you know, antiarrhythmic drugs are a challenge to develop and have been limited in terms of new options over the last several decades. I think it helps us understand the translation between oral and IV. We noticed some acute effects of IV, although nothing particularly profound. I think it helps us in terms of translating the dosing as well as understanding how we can manage these patients more safely, albeit, I think we still are seeing a plateau in terms of effectiveness. That remains among the Achilles’ heels of antiarrhythmic drug therapy, which are the trade-offs between proarrhythmia toxicity and limited effectiveness across patients. 

The transcripts have been edited for clarity and length.  

Reference

1. Steinberg BA, Holubkov R, Deering T, et al. Expedited loading with intravenous sotalol is safe and feasible-primary results of the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry. Heart Rhythm. 2024;21(7):1134-1142. doi:10.1016/j.hrthm.2024.02.046