Improving safety, reducing length of stay for sotalol and dofetilide initiation in AF
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Atrial fibrillation is common, affecting approximately 5.2 million patients in 2010 in the United States, and this is projected to increase to 12.1 million in 2030.
AF is frequently complicated by underlying comorbidities that can increase risk for hospitalization as well as worsen patient’s quality of life. Rate control and rhythm control are available treatment strategies for AF; however, rhythm control has not shown to be superior to rate control in terms of mortality benefit and could possibly increase the risk for hospitalization. As a result, the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines specifically recommend that antiarrhythmic drugs (AADs) for rhythm control should not be continued once AF becomes permanent.
This necessitates the need to develop strategies for safe initiation of AADs for AF either to achieve conversion to normal sinus rhythm (NSR) or for maintenance of NSR following electrical cardioversion.
There are many considerations when initiating dofetilide and sotalol, including obtaining a baseline and sequential ECG prolonged on-treatment QTc, checking baseline potassium and magnesium levels, estimating creatinine clearance (CrCl) for dosing or contraindications, and checking for contraindicated drugs. Given the complexities of AAD initiation, having processes in place to ensure patient safety with appropriate monitoring as well as dosing to reduce rehospitalization and potentially shorten length of stay is imperative. Traditionally, initiation of sotalol or dofetilide is done in the hospital over a 72-hour period.
This article summarizes the role of the pharmacist as a key individual working within a cardiology team to improve patient safety and minimize length of hospital stay when initiating sotalol or dofetilide. However, this article does not focus on the need for rehospitalization and monitoring associated with dose escalation or restarts.
Studies conducted in an outpatient setting have shown that pharmacist involvement in the management of AADs can improve adherence to the currently recommended monitoring parameters as well as enhance patient safety outcomes such as prevention of adverse drug events, which may potentially reduce hospitalization. It is important to note that outpatient sotalol loading is off-label and requires careful monitoring throughout.
A case series study by Chelsea Roberts, PharmD, MS, MBA, BCPS, inpatient operations coordinator at OhioHealth Riverside Methodist Hospital in Columbus, and colleagues evaluated a pharmacist in an AAD clinic:
- Pharmacist-led monitoring of a 3-day outpatient oral sotalol load.
- Twelve patients successfully completed outpatient sotalol loading.
- Overall reduction in the cost of their care in comparison to inpatient loading.
Pharmacist involvement in initiating sotalol
There are preliminary data on some potential options that could be further explored in an inpatient setting to reduce the length of stay including, but not limited to, using IV sotalol, which was previously only approved by the FDA for acute treatment of arrhythmias, replacement of oral sotalol in those who are unable to take oral sotalol and for recurrent atrial arrhythmias. Using an IV sotalol formulation more rapidly achieves concentrations associated with oral formulation steady state and assumes that QTc prolongation is concentration-related so observed prolongation would occur sooner than using an oral loading-dose regimen. This could potentially reduce hospital length of stay.
In March 2020, IV sotalol was approved for the purpose of initiating sotalol therapy in patients with AF to maintain NSR. The approved IV dosing regimen is designed to take into consideration the desired oral maintenance dose and the patient’s CrCl. See the Table on page 24 for recommended baseline tests, monitoring and prescribing considerations for sotalol.
After a 1-hour IV loading dose with QTc interval monitoring every 15 minutes, the load is followed in 4 hours and then 12 hours by oral doses, with QTc monitoring 2 to 4 hours after oral doses. In patients with CrCl greater than 60 mL per minute, it is reasonable to discharge the patient within 20 to 24 hours based on clinical evaluation, renal function and response to therapy. Measurement of QT interval poses a challenge in patients in AF, due to fluctuating R-R interval. While there is not a consensus on how this should be addressed, experts suggest averaging the measured QT interval over 10 beats or measuring the QT intervals following the shortest and longest R-R interval and then diving it by the preceding R-R interval square root.
Sotalol continues to carry a boxed warning for life-threatening proarrhythmia. If the QTc interval prolongs to 500 milliseconds or greater, it is important to reduce the dose or discontinue. Limited data available described below point toward potential for favorable impact, including decreased length of hospital admission, decreased overall admission cost and improved patient satisfaction given its pharmacokinetic parameters.
A retrospective cohort study of 153 patients with AF admitted for oral sotalol initiation evaluated the correlation between dosing schedule and daily hospital costs as well as clinical outcomes during the index hospital stay and for 30 days thereafter. Cost-saving projections of using IV sotalol loading were calculated assuming that 1-day IV sotalol load costs $2,500 to administer. The median length of stay was 2.2 days and cost per day was estimated at $2,931.55. The study reported potential cost savings of $871.55 when using single IV sotalol loading dose compared with a 2-day oral load and $3,803.10 compared with a 3-day loading regimen.
Another study published in Circulation in October 2022 prospectively evaluated 40 patients with AF or atrial flutter, who received IV sotalol followed by two oral doses to achieve steady-state concentrations. This study showed that the QTc interval significantly increased after infusion but stabilized after completion of the two oral doses. No adverse events were reported in these patients. However, there was no additional information on the hospital length of stay or impact on clinical outcomes.
The results of DASH-AF trial were presented at the American Heart Association Scientific Sessions in November 2022. This nonrandomized study aimed to evaluate whether a novel rapid IV loading sotalol regimen followed by the first oral sotalol maintenance dose given 4 hours after the infusion (if QTc acceptable) would result in the same QTc changes as those seen on day 3 after last in-hospital oral sotalol dose in patients stable after AF ablation. If the QTc 2 hours after the first oral dose was acceptable, the patient was discharged.
- Study intervention: 120 patients in IV sotalol group compared to 120 patients in historical cohort receiving 3-day oral loading dose.
- Exclusion criteria:
- left ventricular ejection fraction < 35%;
- baseline QTc > 450 milliseconds;
- heart rate < 50 mL per minute; and
- CrCl < 60 mL per minute.
- Key takeaways:
- No significant difference in QTc or heart rate at baseline or study conclusion between the groups.
- Therapy discontinuation: Four patients in IV group vs. seven in historical cohort discontinued due to severe bradycardia or excessive QT prolongation. Torsades de pointes occurred in one patient.
- Average cost per admission was lower with IV loading compared with oral loading ($5,068 vs. $8,569).
- Small sample size and not powered for safety outcomes.
- Best evidence to support that sotalol IV single dose followed by maintenance dosing is feasible and cost-effective.
Pharmacist involvement in initiating dofetilide
There are only a few studies that have highlighted the benefit of pharmacist involvement in the management of dofetilide initiation and monitoring. In a retrospective cohort study of 30 patients published in 2017 in Annals of Pharmacotherapy, a collaborative pharmacy-cardiology AAD monitoring program showed significant improvement in compliance with recommended monitoring parameters for EEG, potassium, magnesium and renal function monitoring during dofetilide initiation as compared with a historical cohort (98.5% vs. 69.6% of parameters monitored appropriately; P < .05). This can potentially enhance patient safety outcomes such as prevention of adverse drug reactions and reduced hospitalization; however, this study did not assess impact on these clinical outcomes.
A study published in the Journal of Pharmacy Practice in 2020 evaluated the adherence rate after implementation of a pharmacist-managed inpatient dofetilide initiation program in a quasi-experimental root cause analysis (RCA) study of 50 patients before the RCA compared with 50 patients after the RCA.
- Study intervention: The pharmacist or provider initiated the dofetilide order set including the baseline 12-lead ECG, and an electrophysiologist was contacted to obtain QTc at baseline and 2 hours post-dose ECG.
- Key takeaways:
- Improved adherence rate to eight core clinical metrics post-RCA compared with pre-RCA (14% vs. 44%; P < .001) noted. Metrics were:
- pharmacist notes entered within 4 hours of dose administration;
- appropriate renal dosing;
- QTc measurements obtained and reviewed within 2 hours after each dose;
- appropriate dose adjustments based on most recent QTc measurements;
- patient education documentation;
- assessment of potential adverse events such as conduction abnormality;
- drug-drug interactions; and
- electrolyte abnormalities.
- The rate of correcting electrolyte abnormalities improved in post-RCA group from 63% to 93%.
- The frequency of selecting an inappropriately low dose based on renal function was more frequent in the post-RCA group (14% vs. 20%).
- No difference in hospital length of stay was noted (median for both, 3 days; P = .79).
Pharmacists can play an important role
Future trials are needed to validate these findings and to compare IV sotalol to other antiarrhythmics from a safety and tolerability standpoint as well as cost savings potential. It is prudent to note that IV sotalol is one of the first drugs to be approved under the new Model-Informed Drug Development regulatory path, which involves developing and applying exposure-based biological and statistical models derived from historical preclinic and clinic data sources to increase probability of regulatory success. This can improve clinical trial efficiency and further help optimize drug dosing and therapeutic utilization in absence of dedicated trials.
Another niche that is potentially untapped is the role of digital health and use of wearable devices to supplement monitoring and further aid this process to ensure safe and effective loading as highlighted in a poster published by Megan Labreck, PharmD, BCPS, CACP.
- Process:
- Physician refers to the pharmacist to schedule a visit for outpatient sotalol loading.
- First visit: The patient receives education on how to use the Kardia 6L (Kardia Mobile) wearable device to take an ECG and upload the results to send it to the providers. The pharmacist also helps obtain a test ECG and administers the first dose in the clinic.
- Day 1-3: ECG tracings are sent 2 hours post-dose, and sotalol dosing instructions are given by the pharmacist to the patient prior to the next dose.
- Once the loading is complete, patient is to return the device to the clinic and maintenance dose is determined along with the long-term monitoring plan.
- Key points:
- Labreck noted several patients purchase the device to be more intimately involved in their arrhythmia journey.
- In discussion with the author, one caveat highlighted was when the tracings are poor and/or contain lot of artifacts, the patients are generally less willing to come back to the clinic for a 12-lead ECG to confirm the rhythm.
- Additional benefits include decrease in overall cost, increased access to patients with overall improved disease state awareness.
- This provides a team-based care model of safe and effective sotalol loading in an outpatient setting.
In summary, pharmacists can play an important role in monitoring AADs in both inpatient and outpatient settings, which can improve appropriate prescribing metrics, help reduce adverse drug reactions and potentially help reduce length of stay. Additional studies comparing IV sotalol loading to traditional 3-day oral loading on length of stay and safety are needed to encourage adoption of this strategy in routine practice.
- References:
- Abella A. Rapid IV sotalol loading feasible, safe for AF patients. MIMS Pharmacy. Available at: specialty.mims.com/topic/rapid-iv-sotalol-loading-feasible--safe-for-af-patients. Published Dec. 18, 2022. Accessed March 20, 2023.
- Ahmed A, et al. Circulation. 2022;146:A14826.
- Al-Khatib SM, et al. JAMA. 2003;doi:10.1001/jama.289.16.2120.
- FDA. Model-Informed Drug Development Pilot Program. Available at: fda.gov/drugs/development-resources/model-informed-drug-development-pilot-program. Updated Feb. 8, 2022. Accessed March 20, 2023.
- Hindricks G, et al. Eur Heart J. 2021;doi:10.1093/eurheartj/ehaa612.
- January CT, et al. Circulation. 2014;doi:10.1161/CIR.0000000000000040.
- Kibert, JL, et al. J Am Coll Clin Pharm. 2020;doi:10.1002/jac5.1143.
- Knight BP. EP Lab Digest. 2022;22(12):4. Available at: www.hmpgloballearningnetwork.com/site/eplab/letter-editor/same-day-sotalol-loading-atrial-fibrillation. Published December 2022. Accessed March 20, 2023.
- Ko EYJ, et al. J Pharm Pract. 2020;doi:10.1177/0897190019834130.
- Labreck M, et al. Cardiovasc Digital Health J. 2022;doi:10.1016/j.cvdhj.2022.07.014.
- Lakkireddy D, et al. JACC Clin Electrophysiol. 2023;doi:10.1016/j.jacep.2022.11.026.
- Quffa LH, et al. Ann Pharmacother. 2017;doi:10.1177/1060028016669962.
- Roberts C, et al. J Am Pharm Assoc (2003). 2022;doi:10.1016/j.japh.2022.05.028.
- Snider M, et al. Clin Ther. 2009;doi:10.1016/j.clinthera.2009.06.014.
- Somberg JC, et al. Cardiol Res. 2020;doi:10.14740/cr1143.
- Sotalol Hydrochloride Prescribing Information. Available at: www.accessdata.fda.gov/spl/data/a42b9b27-12c0-c0fb-2f63-f344c6de4562/a42b9b27-12c0-c0fb-2f63-f344c6de4562.xml#_1e3e19e5-aba0-1f4e-9eeb-2a43d135bd89. Accessed March 20, 2023.
- Sotalyze Prescribing Information. Available at: sotylize.com/docs/sotylize-prescribing-information.pdf. Accessed March 20, 2023.
- Tikosyn (dofetilide capsules) Prescribing Infor-mation. Available at: www.accessdata.fda.gov/spl/data/c16c9652-9114-4b39-b240-bc0cb85b8b8d/c16c9652-9114-4b39-b240-bc0cb85b8b8d.xml. Accessed March 20, 2023.
- Tsao CW, et al. Circulation. 2022;doi:10.1161/CIR.0000000000001052.
- Varela DL, et al. J Cardiovasc Electrophysiol. 2022;doi:10.1111/jce.15342.
- For more information:
- Tanvi Patil, PharmD, BCPS, is associate chief of pharmacy, Clinical Services and Education, and PGY1 Pharmacy Residency Director and Clinical Pharmacy Practitioner – Cardiology at Salem Veterans Affairs Health Care System, Virginia.
- Stacey Zysk, PharmD, is clinical pharmacist at Salem Veterans Affairs Health Care System, Virginia.
- Kezia Timmons, PharmD, is a PGY2 psychiatry pharmacy resident at Salem Veterans Affairs Health Care System, Virginia.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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