Multicenter Analysis of Dosing Protocols for Sotalol Initiation

Abstract

Sotalol, a Vaughan-Williams Class III antiarrhythmic medication, is used to manage atrial arrhythmias. Due to its QT-prolonging effect and subsequent increased risk of torsade de pointes, many centers admit patients during the initial dosing period. Despite its widespread use, little information is available regarding dosing protocols during this period. In this multicenter investigation, dosing protocols in patients initiating sotalol therapy were examined to identify predictors of successful sotalol initiation. Over a 4-year period, patients admitted to 5 hospitals in the United States for inpatient telemetry monitoring during initiation for nonresearch purposes were enrolled. A 3-day course of 5 of 6 doses of sotalol was considered successful completion of the loading protocol. Of the 213 enrolled patients, over 90% were successfully discharged on sotalol. Significant bradycardia, ineffectiveness, and excessive QT prolongation were reasons for failed completion. Absence of a dose adjustment was a strong predictor of successful initiation (odds ratio: 6.6, 95% confidence interval: 1.3–32.7, P = .02). Hypertension, use of a calcium channel blocker, use of a separate β-blocker, and presence of a pacemaker were predictors of dose adjustments. Marginal structural models (ie, inverse probability weighting based on probability of a dose adjustment) verified that these factors also predicted successful initiation via preventing any dose adjustment and suggests that considering these factors may result in a higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication. The study findings suggest that factors predicting need for dose adjustment can be used to identify patients who could undergo outpatient initiation. Prospective studies are needed to verify this approach.

Introduction

Sotalol is a Vaughan-Williams (VW) Class III antiarrhythmic agent that is used in the treatment of atrial^1–3 and ventricular arrhythmias.^4–8 Composed of a racemic mix of 2 isomers, the d- and l isomers of sotalol work together to prolong repolarization (d- and l-isomer) along with nonselective β-blocking properties (l-isomer). This property is significant as use of isolated d-Sotalol was found to be associated with increased mortality in patients with heart failure in the Survival With ORal D-sotalol (SWORD) study,⁹ while use of the racemic mix is generally considered to be safer in this population. Like other VW Class III agents, sotalol displays reverse use dependence properties, in which heart rate and the QT interval are inversely related such that at lower heart rates, the QT interval prolongs.¹⁰ At doses between 160 and 640 mg/d, sotalol increases QT interval by 40 to 100 milliseconds.¹¹ In a cohort of 541 patients obtained from electronic medical record review starting sotalol, Weeke el al found that the average ± standard deviation change in corrected QT interval (Bazett formula) was highly variable (3 ± 42 milliseconds at 2 hours and 11 ± 37 milliseconds at ≥48 hours) following the initial dose.¹²

Due to these properties of sotalol, there is a 1% to 4% incidence of developing adverse QT prolongation and subsequent torsade de pointes (TdP) in a dose-dependent fashion,^13–21 with risk factors including dose above 320 mg/d, creatinine clearance <40 mL/min,²² history of sustained VT/VF, history of heart failure or coronary artery disease, and female gender placing people at higher risk.¹⁴ As a result, most, but not all, institutions require admission to a monitored telemetry unit for initiation and dose adjustments of sotalol. The Food and Drug Administration also has a label recommendation for initiating sotalol,²³ which includes a box warning and recommended minimum of 3 days in-hospital monitoring requirement based on the degree of QTc prolongation being linearly associated with sotalol concentrations—the 3 days requirement corresponds to the time to reach maximum steady-state exposure (concentrations) for sotalol under a constant dosing regimen and thus maximum QTc prolongation.²⁴ However, despite multiple observational studies examining patterns of sotalol initiation,^12,14,25,26 no single algorithm exists to guide initiation of sotalol therapy. In this investigation, we examine patterns of sotalol initiation across multiple institutions nationwide to identify predictors of successful initiation.

Methods and Materials

Population

The National Torsade de Pointes Consortium is composed of representatives from the Massachusetts General Hospital, University of Colorado Hospital, Cleveland Clinic, Beth Israel Deaconess Medical Center, and the Mayo Clinic. Eligibility criteria for this study included all patients who were admitted to the hospital for in-patient telemetry monitoring for sotalol initiation for nonresearch purposes and were enrolled at these centers over the period from June 8, 2014, and September 18, 2018. Patients previously taking sotalol and undergoing admission for dose adjustments were excluded. Clinical information was collected on patients over the duration of the hospitalization, including electrocardiography (ECG), laboratory test values, and clinical events. As this was an observational study, decisions about dose adjustments were made entirely at the discretion of the treating physician, and there was no specific protocol that providers were asked to follow in making dose adjustments for patients. Data were collected in a RedCap database; Massachusetts General Hospital served as the data coordinating center for this investigation. This study is registered with the U.S. National Library of Medicine ClinicalTrials.gov ( NCT02439658). The study was approved by institutional review boards at all participating institutions.

Study Parameters

Baseline data were collected prior to initiation of sotalol and included age, sex, demographic information, race, ethnicity, height, weight, body mass index (BMI), past medical history of atrial fibrillation (AF), ventricular tachycardia, essential hypertension, coronary artery disease, congestive heart failure, presence of a pacemaker or implantable cardioverter-defibrillator, routine laboratory test values (serum potassium, magnesium, and creatinine), assessment of left ventricular function (ie, ejection fraction) based on transthoracic echocar-diography, nuclear imaging, or cardiac magnetic resonance imaging, and standard ECG rhythm and measurements (heart rate, PR, QRS, QT intervals). Electrocardiographies were over-read for accuracy by a cardiologist member of the research team. Underlying atrial rhythm was categorized as AF, flutter, or tachycardia (AF); sinus or atrial paced (SR) rhythm; or unknown (UNK) if both sinus and atrial arrhythmias were present or if junctional or ventricular paced rhythm was present. An ECG was also categorized as UNK if greater than 3 atrial or ventricular premature complexes were noted. UNK ECGs were excluded from ECG analysis (intervals and rhythm), although other clinical information for these patients was included. The QT was corrected using Fridericia²⁷ formula (QT/RR interval)^1/3. All patients were included regardless of existence of prior bundle branch block or ventricular pacing, with QRS duration examined as a covariate. Data were also collected regarding timing of electrical or chemical (spontaneous) cardioversion.

Outcome

We considered discharge of a patient on sotalol to be a successful initiation of sotalol; any patient who was not discharged on sotalol was considered a protocol failure. Reasons for failure were categorized by study investigators into “ineffective,” “bradycardia,” “QT prolongation,” “other intolerance/side effect,” and “other/unknown,” based on review of clinical charts, although the decision about continuation or cessation of sotalol was made by the treating physicians, independently of the research study.

Analysis

All analyses were conducted on a single data set downloaded from the central RedCap database on September 20, 2018. Univariate analysis was conducted using logistic regression with successful discharge on medication as the outcome to identify individual predictors of successful initiation. Due to the limited number of unsuccessful initiation protocols (under-powered), multivariate analysis was not performed with successful initiation as the outcome. To examine causal pathway for factors leading to dose adjustment, we used a marginal structural model^28,29 based on inverse probability weighting for dose adjustment (See Supplemental Material, for details). First, stepwise logistic regression was performed by dose across all predictors in order to identify those predicting a single dose adjustment at significance level of P < .1. Then, generalized estimating equations (GEEs) were applied using a logit link and subject-level clustering across doses, to examine the inverse of the predicted probability of a dose adjustment by dose for each participant on probability of successful initiation of sotalol. All statistical analysis was performed using Stata IC (version 15.1; StataCorp, LLC, College Station, Texas).

Results

Between June 8, 2014, and September 18, 2018, 213 participants were admitted to 5 participating medical centers (range 1–100 per center). Atrial fibrillation was the most common indication, and most patients were in AF at the start of the initiation protocol (Table 1). Sotalol was initiated in more men than women, although there were no statistically significant differences in successful completion of the loading protocol between sexes.

Table 1.

Patients Characteristics.

	Successful Load (n = 193)	Unsuccessful Load (n = 20)	Total (N = 213)
Age (years)	65.9 ± 10.6	69.2 ± 8.5	66.2 ± 10.5
Gender (male)	128 (66.3%)	10 (50%)	138 (64.8%)
Ethnicity
• Hispanic/Latino	7 (3.6%)	1 (5%)	8 (3.8%)
• Non-Hispanic/Latino	182 (94.3%)	19 (95%)	201 (94.4%)
• Unknown	1 (0.5%)	0 (0%)	1 (0.5%)
Race
• Caucasian	187 (96.9%)	19 (95%)	206 (96.7%)
• African American or black	3 (1.6%)	0 (0%)	3 (1.4%)
• Asian	0 (0%)	1 (5%)	1 (0.5%)
• Unknown/not reported	3 (1.6%)	0 (0%)	3 (1.4%)
Medications on admission
• β-Blocker	105 (54.4%)	5 (25%)	110 (51.6%)
• Calcium channel blocker	32 (16.6%)	1 (5%)	33 (15.5%)
• Diuretic	43 (22.3%)	6 (30%)	49 (23.0%)
Medical history
• Atrial fibrillation	170 (88.1%)	15 (75%)	185 (86.9%)
• Ventricular tachycardia	30 (15.5%)	3 (15%)	33 (15.5%)
• Heart failure	30 (15.5%)	4 (20%)	34 (16.0%)
• Hypertension	96 (49.7%)	16 (80%)	112 (52.6%)
• Type II diabetes mellitus	18 (9.3%)	1 (5%)	19 (8.9%)
• Coronary artery disease	46 (23.8%)	4 (20%)	50 (23.5%)
• Pacemaker	18 (9.3%)	1 (5%)	19 (8.9%)
• Implantable cardioverter-defibrillator	25 (13.0%)	1 (5%)	26 (12.2%)
Indication for sotalol loading: atrial fibrillation	166 (87.8%)	15 (83.3%)	181 (87.4%)
Most recent LV EF assessment
• LV EF > 35%	145 (89.0%)	14 (87.5%)	159 (88.8%)
• LV EF ≤ 35%	18 (11.0%)	2 (12.5%)	20 (11.2%)
Previously on sotalol	14 (7.3%)	2 (10%)	16 (7.6%)
Admission ECG
• Sinus rhythm or atrial paced	92 (49.7%)	7 (36.8%)	99 (48.5%)
• HR (mm)	84.5 ± 23.7	85.1 ± 24.5	84.6 ± 23.7
• PR (mm)	182.1 ± 40.2	211.9 ± 74.7	184.6 ± 44.4
• QRS (mm)	105.6 ± 27.8	108.6 ± 35.4	105.8 ± 28.5
• QTc (Fridericia)	451.9 ± 37.7	468.9 ± 40.4	466.2 ± 50.9
Pertinent laboratory data
• Potassium	4.3 ± 0.4	4.1 ± 0.4	4.3 ± 0.4
• Magnesium	1.9 ± 0.2	2.0 ± 0.2	2.0 ± 0.2
• Serum creatinine (mg/dL)	0.97 ± 0.27	0.97 ± 0.17	0.97 ± 0.26
Sotalol loading
• Starting dose
• 40 mg	6 (3.1%)	2 (10%)	8 (3.8%)
• 80 mg	120 (62.2%)	14 (70%)	134 (62.9%)
• 120 mg	65 (33.7%)	4 (20%)	69 (32.4%)
• 160 mg	2 (1.0%)	0 (0%)	2 (0.9%)
• Median Number of doses received (IQR)	5 (5–6)	4 (3.5–5)	5 (5–6)
• No dose adjustment (after 5–6 doses)	111 (57.3%)	2 (0%)	113 (53.1%)
• Cardioverted electrically	83 (43.0%)	5 (25%)	88 (41.3%)
• Spontaneously converted	17 (9.1%)	10 (50%)	27 (12.7%)
• Discharged off sotalol	0 (0%)	20 (100%)	20 (9.4%)

Abbreviations: ECG, electrocardiogram; HR, heart rate; IQR, interquartile range; LVEF, left ventricular ejection fraction.

A total of 113 patients (53.1%) completed the initiation protocol without any adjustment in the dose—40 mg twice daily (BID): 1 (0.9%), 80 mg BID: 64 (56.6%), 120 mg BID: 47 (41.6%), and 160 mg BID: 1 (0.9%). Sixty-six patients (31.0%) had at least one adjustment over the protocol, and 34 patients (16.0%) stopped the protocol before reaching the fifth or sixth dose. Figure 1 shows the various dosing trajectories for patients who had at least one change and average numbers by dose. There was no obvious other pattern than no adjustment through the population, although the most common doses were 80 and 120 mg, and most adjustments were increasing or decreasing between these values. Twenty patients (9.4%) were not discharged home on the medication. Of these, 11 had stopped prior to the fifth dose, 2 had no dose adjustment and stopped after the fifth dose, and 7 had at least 1 dose adjustment and stopped after the fifth dose. Of the reasons for unsuccessful initiation, the most common were “ineffective” (8 patients), “QT prolongation” (7 patients), “bradycardia” (4 patients), and “other/unknown” in 1 patient.

Figure 1.

Dose adjustment patterns for sotalol. Numbers indicate patients receiving that dose at each time point, which are separated by ~12 hours as per routine. Not shown are patients who had no dose adjustment during the hospitalization.

A total of 105 (51.5%) patients were in AF or flutter on initiation of sotalol, and of these, 61 (66.3%) underwent electrical cardioversion and 20 (19.1%) spontaneously converted to sinus rhythm. There was no significant effect of electrical or spontaneous conversion to sinus on the probability of discharge on sotalol.

In univariate logistic regression, patients with no adjustment in the dose were more likely to be discharged on sotalol than those who had at least one dose change (odds ratio [OR]: 6.6, 95% confidence interval [CI]: 1.3–32.7, P = .021), and patients with a higher starting dose had a higher probability of discharge (120 mg: 94.2% [95% CI: 88.7%−99.7%], 80 mg: 89% [95% CI: 84.4%−94.7%], 40 mg: 75% [95% CI: 45.0%−1.05%]), although the latter difference did not reach statistical significance (P = .22). Of the predictors examined (Table 2), lack of any dose adjustment was among the most predictive of successful initiation. History of hypertension and use of a separate β-blocker were also predictive of successful discharge on sotalol, although it is possible that the mechanism of these factors was by decreasing the dose changes of sotalol (see below).

Table 2.

Prediction of Successful Initiation of Sotalol (Based on Logistic Regression).

	Odds Ratio	Confidence Interval	P Value
No dose adjustment	6.58	1.33–32.71	.021
Indication	0.69	0.19–2.58	.584
Hypertension	0.25	0.08–0.77	.016
Type II diabetes mellitus	1.95	0.25–15.47	.526
Permanent pacemaker	1.95	0.25–15.47	.526
Heart failure	0.74	0.23–2.35	.606
β-blocker	3.58	1.25–10.24	.017
Calcium channel blocker	3.78	0.49–29.23	.203
Low ejection fraction	0.87	0.18–4.14	.860
Sinus rhythm	1.70	0.64–4.50	.289
Heart rate	1.00	0.98–1.02	.917
QTc (Fridericia)	1.00	0.99–1.00	.297

Since dose adjustments appeared to play a significant role in the overall successful initiation of sotalol, we examined the role of this decision as a marginal structural model, using inverse probability weighting for dose adjustment. After reshaping the data set to allow modeling by dose number, we identified that the dose number (OR: 0.74, 95% CI: 0.64–0.88), presence of hypertension (OR: 2.0, 95% CI: 1.2–3.4), use of calcium channel blocker (OR: 2.1, 95% CI: 1.2–3.8), use of a separate β-blocker (OR: 0.63, 95% CI: 0.38–1.0), and presence of a pacemaker (OR: 0.17, 95% CI: 0.04–0.72) were all predictors for making a dose adjustment at P < .1. An OR greater than 1 indicates an increased likelihood of making a dose adjustment; an OR less than 1 indicates a lower probability of making an adjustment. From the multivariate logistic regression model, we calculated inverse probability of a dose adjustment by dose number and examined the role in predicting successful initiation of sotalol using GEEs. This model demonstrated that predictors of dose adjustment were also successful at predicting the probability of successfully completing the initiation protocol of sotalol (OR: 0.977, 95% CI: 0.960–0.995, P = .014).

Discussion

In this multicenter observational study of sotalol initiation protocols, we found that regardless of the dose protocol, the vast majority of patients (>90%) were able to successfully initiate sotalol during the loading protocol and that over 50% of the population was able to do so without any adjustments to the medication. We found a large range of variability in the dose adjustments made during initiation of sotalol but also found that patients in whom dose adjustments were made were less likely to be discharged on the medication. Several factors were associated with making dose adjustments, including presence of a pacemaker, β-blockers or calcium channel blockers, and hypertension, and could be examined in future prospective studies aimed at minimizing dose adjustments toward the goal of improving likelihood of sotalol initiation, as well as targeting specific patients for outpatient initiation.

Unlike the related VW class III antiarrhythmic medication, dofetilide, the initiation protocol for sotalol is less well defined, or adhered to, and at some institutions, patients being initiated on sotalol are not admitted for any monitoring during the initiation process at all. Several groups examined the safety of inpatient sotalol initiation over 2 decades ago and noted a higher rate of events than we identified. Maisel and colleagues examined adverse cardiac events in 72 trials of sotalol 80 mg twice a day for AF²⁵ and found that adverse cardiac events occurred in 18%: bradyarrhythmias occurred in 8 (11%), ventricular arrhythmias in 2 (2.8%), QT prolongation in 1 (1.4%), and 2 other events (unspecified). The risk was greatest within the first 24 hours of therapy and in patients with a previous myocardial infarction.²⁵ Chung et al also examined the risks of sotalol initiation in 120 patients admitted to a single center²⁶ and found that complications occurred in 25 patients (21%), which triggered a change in therapy (dose reduction or cessation) in 21. The most common complications were bradycardia in 20 (including a heart rate below 40/minute in 13), excessive prolongation of the QT interval in 8, and new or increased ventricular arrhythmias in 7 (including 2 cases of TdP). Complications occurred within the first 3 days in 22 of the patients (88%).²⁶ In the more contemporary era, Weeke and colleagues also examined sotalol initiation using electronic health record data and noted a discontinuation rate of 12%, with 31% due to prolonged QT interval.¹² The latter study is interesting in that it was almost 15 years after the former 2, with protocol cessation primarily due to QT interval prolongation. That the former 2 studies identified a rate of complications higher than our study and that of Weeke et al’s, may reflect greater attention to dose effects in the more contemporary period, although none of the earlier studies examined dose-by-dose granularity as we did, and thus, we cannot determine this effect precisely.

Our finding that over half of patients were able to successfully initiate sotalol without a single dose adjustment has potential implications for future efforts at outpatient sotalol initiation protocols. Noteworthy is that patients with a pacemaker present were significantly less likely to have a dose adjustment and more likely to successfully initiate sotalol than those without, perhaps due to less bradycardia, which was a key reason for failure of initiation. Given the continued advances in remote monitoring of cardiac implantable devices,^30,31 as well as development of wearable/portable devices for measuring QT interval,^32,33 it seems that our findings support the possibility that these patients could undergo outpatient initiation of sotalol, although more work is clearly needed.

The role of dose adjustments in patients being initiated on sotalol should be contrasted with the other VW class III medication for which patients are admitted for initiation, dofetilide. For one, patients starting dofetilide are generally started at the highest dose, with adjustments downward based on QT interval.³⁴ As observed in this study, most patients initiated on sotalol are started at 80 mg BID, which is the lowest dose at which antiarrhythmic activity (class III) takes place, and either increased or maintained at the same dose over the course of the 3 days of monitoring. Importantly, we found that making any dose adjustments decreased the probability of successful initiation. Of course, whether the decision to make a dose adjustment was made by providers seeking to achieve a predetermined dose or whether the decision was made to adjust the dose because of concerns of toxicity or ineffectiveness that ultimately led to discontinuation of the medication could not be determined by our study design. Within the confines of an observational study, such a determination cannot be made definitively and requires a prospective trial with a predetermined dosing protocol to define the direction of causality. We believe this future investigation would be important, as dose adjustment targeting ineffectiveness rather than toxicity could potentially be made in an outpatient setting over a longer time period, as is done in other non-class III antiarrhythmics. Such an approach could be much more cost-effective than present standards for inpatient monitoring.

There are several important limitations in this investigation. First, as noted above, because our study was observational in nature, we were unable to draw more definitive conclusions about the role of dose decisions in successful initiation of sotalol. There is an obvious issue of “cause-and-effect” related to making these adjustments, and while certain findings, such as the presence of a pacemaker decreasing the probability of a dose adjustment and increasing probability of successful initiation of sotalol, make intuitive sense, others, such as the associations of calcium channel blockers and β-blockers with dose adjustments, are more difficult to explain. These associations would seem to be more likely to be spurious, and likely due to other unmeasured effects specific to certain patients, but only through future prospective study can we know for certain. Second, we did not have medium- or long-term follow-up and thus were unable to determine whether patients who did successfully initiate sotalol had long-term success with the medication and free of complications. Such follow-up is of obvious importance for drawing conclusions; however, understanding the factors that impact successful initiation in the short term is also important. For both patients and providers, the time wasted when a patient is admitted for sotalol initiation and then leaves without being on the medication is a burden both in time and money. Efforts to minimize this outcome are clearly desired, regardless of whether sotalol has long-term success in management of atrial or ventricular arrhythmias. Third, although in our models QTc was not a critical factor in the dose decision and/or the probability of a successful load, clinical experience, and prior investigations,^12,22 has highlighted this factor as a critical component in the dose decision. It is possible that the greater attention paid to QTc in the decision to initiate sotalol, as well as inaccuracy in measurement of QTc among patients with AF (>50% of our population), may have played some role in our findings, we suspect that other strategies may be needed experimentally to understand the use of QTc in the clinical decision beyond the models applied in this investigation. Finally, our use of a multicenter study design had limitations in the depth of information that could be collected about patients. Newer approaches by our group³⁵ and others to use machine learning to analyze high-density data,^36–38 such as from telemetry, implanted cardiac devices, and other continuous data streams, could provide greater prediction than standard ECG or clinical factors but are more difficult to collect across institutions and monitoring platforms. In addition, application of intravenous (IV) sotalol, with IV to oral transition, could potentially reduce hospitalization duration and costs.²⁴ These future approaches could open a treasure trove of data and possibilities that could provide additional guidance on dose management for medications like sotalol.

Conclusion

In conclusion, we found that the majority of contemporary patients admitted at multiple medical centers for monitoring during initiation of sotalol were successfully discharged on the medication, including over half without a single dose change. We found that among other factors, making dose adjustments was a key risk factor for failed initiation and that patients with pacemakers already implanted were less likely to have dose adjustments and more likely to be discharged on sotalol. Further prospective studies are needed to examine the role of dose protocols toward the possibility of safe outpatient sotalol initiation.