Economics and outcomes of sotalol in‐patient dosing approaches in patients with atrial fibrillation

Abstract Introduction There exists variability in the administration of in‐patient sotalol therapy for symptomatic atrial fibrillation (AF). The impact of this variability on patient in‐hospital and 30‐day posthospitalization costs and outcomes is not known. Also, the cost impact of intravenous sotalol, which can accelerate drug loading to therapeutic levels, is unknown. Methods One hundred and thirty‐three AF patients admitted for oral sotalol initiation at an Intermountain Healthcare Hospital from January 2017 to December 2018 were included. Patient and dosing characteristics were described descriptively and the impact of dosing schedule was correlated with daily hospital costs/clinical outcomes during the index hospitalization and for 30 days. The Centers for Medicare and Medicaid Services reimbursement for 3‐day sotalol initiation is $9263.51. Projections of cost savings were made considering a 1‐day load using intravenous sotalol that costs $2500.00 to administer. Results The average age was 70.3 ± 12.3 years and 60.2% were male with comorbidities of hypertension (83%), diabetes (36%), and coronary artery disease (53%). The mean ejection fraction was 59.9 ± 7.8% and the median corrected QT interval was 453.7 ± 37.6 ms before sotalol dosing. No ventricular arrhythmias developed, but bradycardia (<60 bpm) was observed in 37.6% of patients. The average length of stay was 3.9 ± 4.6 (median: 2.2) days. Postdischarge outcomes and rehospitalization rates stratified by length of stay were similar. The cost per day was estimated at $2931.55 (1. $2931.55, 2. $5863.10, 3. $8794.65, 4. $11 726.20). Conclusions In‐patient oral sotalol dosing is markedly variable and results in the potential of both cost gain and loss to a hospital. In consideration of estimated costs, there is the potential for $871.55 cost savings compared to a 2‐day oral load and $3803.10 compared to a 3‐day oral load.


| BACKGROUND
Atrial fibrillation (AF) is the most common arrhythmia, with a lifetime incidence estimated at~20%. 1 The total number of cases of AF in the United States is expected to exceed 2.5 million by the year 2030 and 7.5 million by 2050. 1,2 AF carries significant morbidity and is one of the leading causes for hospitalization in the United States, with annual AF admissions exceeding 450 000 cases per year since 2010. 1,2 The cost burden of AF on the US Healthcare System is huge, with an estimated $10 billion spent managing AF in 2014. 3 With increasing numbers of new AF cases each year, the financial burden imposed by AF continues to grow.
Antiarrhythmic drugs (AADs) still play a key role in the rhythmbased management of AF; nonetheless, there remains a need to better understand protocols to administer these medications and monitor for side effects safely and effectively. The class III AAD sotalol is often loaded in the in-patient setting, which requires several days of hospitalization for monitoring of drug side effects until steady state. In-patient initiation of AAD therapy has been identified as a high-cost burden aspect of AF-related care. 4 The cost associated with sotalol is particularly concerning, as it has risen considerably over the years and is only expected to continue to rise. A 3-day hospitalization for sotalol initiation cost approximately $3500 in 2009 and increased to $10 000-$12 000 in 2019. 5 The single greatest expense incurred during a patient's admission for sotalol initiation is room and board, with costs of approximately $2000-$3000 per night. Strategies aimed at reducing hospital length of stay may help drive down costs associated with sotalol initiation.
Despite a Food and Drug Administration (FDA) black box warning and societal recommendations that advocate for a 3-day hospitalization and inpatient monitoring for QT prolongation and ventricular arrhythmias during the initiation of sotalol therapy, there exists considerable variability in how this drug is loaded in clinical practice. 6 The impact of this variability on hospitalization costs and patient outcomes is unknown. One potential avenue for shortening a patient's length of stay would be to administer sotalol in a formulation that allows for more rapid achievement of steady-state concentration, facilitating the earlier detection of potential side effects.
Intravenous (IV) sotalol was initially given FDA approval for use in 2010 as a substitute for oral therapy in patients unable to take medications orally. In March 2020, IV sotalol received FDA approval for use as part of the drug's initial loading protocol. 7,8 The IV administration shortens the time to steady-state plasma concentration from 3 days to just 1-2 days (single IV dose plus 1-2 oral doses). The ability to reduce hospital length of stay could significantly reduce costs associated with in-patient sotalol initiation and mitigate the overall economic burden that AF imposes on the healthcare system. Furthermore, protocol-based IV sotalol administration may eliminate the dosing variability that currently exists in clinical practice and potentially imparts the risk of drug underdosing or overdosing.
This study aims to investigate the average length of stay for oral sotalol initiation admissions and evaluate the costs and clinical outcomes stratified according to initial hospitalization length of stay.
Additionally, the study will quantify the sotalol dose at discharge to help provide clarity regarding potential underdosing or overdosing of drug therapy. Finally, this study will explore the cost impact of a 1-day IV sotalol load to determine if there is a potential for cost savings that might be conferred by switching from an oral to IV sotalol loading protocol secondary to a shortened hospital stay.  Table 1 for complete list). Measurements of body mass index and ejection fraction were recorded. Use of prior medications and sotalol dosing were available. These variables were determined by electronic medical records and ICD-9/10 codes that pre-dated index hospitalization.

| Endpoints and outcome measures
In-patient outcomes evaluated were those related to sotalol dosing, which included length of stay, electrocardiographic changes in response to sotalol initiation (increased Q wave, R wave and S wave (QRS) duration and QT/corrected QT interval (QTc) prolongation), the presence of significant bradycardia, stroke, and death. The postdischarge outcomes assessed were death, recurrent AF or AFL, stroke, ventricular tachycardia (VT), ventricular fibrillation (VF), Torsades de Pointes, QTc prolongation, bradycardia, emergency department (ED) visit, and any hospital readmission. Death was T A B L E 1 Baseline characteristics, medications, and in-hospital treatments and procedures

| Statistical analysis
The
Similarly, potential drug underdosing could also explain the lack of any ventricular arrhythmias during follow-up. One prior study reported a 5.8% incidence of new or increased ventricular arrhythmias in response to sotalol initiation. 13 In that study, the median initiation Bradycardia and QTc prolongation were the most common inpatient side effects associated with sotalol initiation, occurring in approximately 20%-30% of patients during the index hospitalization.
Despite the high rates of bradycardia and QTc prolongation, no ventricular arrhythmias occurred during hospitalization.
Postdischarge bradycardia and QTc prolongation were also common, occurring in 30%-40% of patients at 12-month follow-up.
Long-term treatment failure (recurrent AF or AFL) was also common, prior studies with IV sotalol initiation has been estimated between $3000 and $4000 when compared with a 3-day oral load. 1,5,8 In the present study, we found the average cost per 3-day admission for oral sotalol initiation was $12 466 (median: $8569), with the greatest expense coming from the hospital room itself (45%-66% of total hospitalization costs). Hospital room costs are so high that they markedly exceeded the costs of the physician, nursing, and pharmacy labor combined (average $5666 vs. $1462, over the course of a 3-day admission).
The average cost of admission reported in our study is compar-

| In consideration of IV sotalol
We proposed a 1-day IV sotalol loading protocol similar to that proposed by Somberg et al., 11 where an initial IV dose of sotalol was administered over 1 h, followed by the first oral dose 5 h after the infusion and a second oral dose 12 h after the first oral dose.
Pharmacokinetic-pharmacodynamic models were used to ensure that peak sotalol plasma concentrations were achieved after each dose, thereby providing three separate opportunities to monitor for adverse drug effects at peak sotalol concentration over the course of a 24-h hospitalization. We projected cost savings using this IV loading

| Study limitations
The superior cost economics of IV sotalol over oral sotalol should be considered hypothesis-generating, as they are based on projected cost savings analyses. Prospective studies that implement the proposed IV sotalol loading protocols need to be performed to evaluate the real-world cost economics of IV sotalol and obtain a better understanding of the IV formulation's impact on drug efficacy and clinical outcomes.
The current study also did not track certain outcomes that may have been helpful for assessing sotalol's efficacy and safety profile, such as the percentage of patients who required electrical cardioversion in addition to sotalol during index hospitalization and the rate of sotalol discontinuation throughout the follow-up period. Data for readmission diagnoses were also lacking, making it impossible to determine whether readmissions were predominantly driven by recurrent arrhythmias, other cardiac comorbidities (e.g., acute coronary syndrome and heart failure), or unrelated noncardiac medical conditions.

Furthermore, EKG QT, and QTc intervals reported in this analysis
were measured by computer automation as opposed to having a trained MD interpret the true QT and QTc intervals. This could lead to some inaccuracy in the reported QT/QTc values. As QT/QTc were used as parameters to make decisions regarding oral sotalol doses and loading, this could lead to some minor inaccuracies in the data.
The use of ICD-9/10 codes is successful in their ability to capture data only as far as they are coded correctly. However, this is a commonly used method for capturing data in retrospective research, one that holds up when compared with adjudication by comprehensive medical record review. [15][16][17] The FDA approval of IV sotalol is based on translational research models and has not been directly studied in humans, and there are concerns that IV administration of sotalol may overshoot serum drug concentrations and increase the risk of QTc prolongation and ventricular arrhythmias-risks that may not be accounted for in translational research models. 6 Reassuringly, a meta-analysis conducted to assess the risk of ventricular arrhythmias following the rapid administration of high-dose IV sotalol (1.5 mg/kg or max 100 mg IV infused over <30 min) found a similar, if not slightly lower, risk of ventricular arrhythmias relative to oral sotalol. 18 While these findings lend credibility to the observations of the safety of IV sotalol and the rapid achievement of a therapeutic steady-state plasma drug concentration, caution must still be maintained as hospitals begin to adopt IV sotalol loading protocols in clinical practice. Physicians need to remain vigilant and closely monitor for arrhythmias and other serious potential side effects that could occur as a result of this new route of administration for the long-standing and familiar AAD, sotalol.

| Future directions
This study compared hospitalization costs that were derived using real-world data from patients admitted for oral sotalol initiation against projected/theoretical cost savings that could be derived using a proposed IV sotalol loading protocol. The projected cost savings reported in the present study support efforts to implement an IV sotalol loading protocol, but real-world data from patients treated with IV sotalol are still needed to determine whether proposed IV loading protocols can truly be completed over the course of a single overnight hospitalization and to confirm the clinical efficacy and safety of IV sotalol loading protocols.
Additionally, some centers, particularly those outside of the United States, have implemented novel protocols for outpatient sotalol loading that employ ambulatory cardiac monitoring (e.g., cardiac event monitors, or implantable electronic pacemaker or defibrillator data) to monitor for ECG abnormalities such as QT prolongation and ventricular ectopy in the outpatient setting while loading patients with sotalol. 19 If these novel approaches for outpatient sotalol loading prove safe and effective, then they may provide viable and cost-effective alternatives to both oral and IV inpatient loading protocols. Additional studies will be needed on both IV sotalol and these novel outpatient oral sotalol loading strategies to determine the feasibility, efficacy, safety, and costs associated with each to determine the optimal drug formulation and loading protocols for this medication.
VARELA ET AL.

| CONCLUSIONS
Costs associated with the management of AF continue to rise as treatment options for this condition become increasingly complex.
The costs incurred during in-patient admission for AAD loading have rapidly increased over the years and represent a huge financial burden to our healthcare system, while the costs of AADs themselves have remained fairly stable. IV sotalol offers an opportunity to mitigate some of these costs by expediting the drug initiation process and facilitating a faster time to hospital discharge. In addition to the financial benefits of reducing hospitalization time, a shorter hospital stay may also decrease the risk of iatrogenic complications tied to hospitalization, may improve patient satisfaction and willingness to initiate AAD therapy, and, when introduced with a pharmacokinetic-guided protocol for administration, may reduce variability in dosing and the potential for inadvertent under-or overdosing.

ACKNOWLEDGMENT
This study was funded by AltaThera Pharmaceuticals, LLC.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available by request from Intermountain Healthcare and for the economics analysis from Altathera. Restrictions apply to the availability of these data, which were used under permission from these organizations.