Patterns of Dofetilide Use for the Treatment of Atrial Fibrillation

DOI: 10.19102/icrm.2016.070703

PRASHANT D. BHAVE, MD¹, SHARON SHEN, MD², ROD PASSMAN, MD, MSCE³, JEFFREY J. GOLDBERGER, MD⁴ and MICHAEL H. KIM, MD⁵

¹University of Iowa Hospitals and Clinics, Division of Cardiology, Iowa City, IA

²Vanderbilt University, Division of Cardiology, Nashville, TN

³Northwestern University Feinberg School of Medicine, Division of Cardiology, Chicago, IL

⁴University of Miami School of Medicine, Division of Cardiology, Miami, FL

⁵SIU School of Medicine, Division of Cardiology, Springfield, IL

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ABSTRACT. Patterns of dofetilide use for rhythm control in atrial fibrillation (AF) have not been well elucidated. The purpose of this study was to characterize dofetilide use on initiation at an academic medical center. Retrospective data on consecutive patients admitted for dofetilide initiation at our institution from 2004 to 2009 were abstracted. Dofetilide initiations were assessed with respect to concordance with the tiered maintenance of sinus rhythm (MSR) algorithm for anti-arrhythmic drug (AAD) use outlined in the 2011 AHA/ACC/HRS guidelines for the management of AF. Follow-up data were collected through November 2012. A total of 122 patients were included. The mean age was 62 ± 13 years. Females constituted 34% (42/122) of the cohort. Eighty patients (66%) were in AF at the time of admission. In patients with no prior AAD exposure (56/122; 46%), dofetilide use was significantly more discordant with the 2011 MSR guidelines than for patients in whom dofetilide was used as a second-line agent (46% discordant versus 15% discordant, p<0.001). Rates of chemical cardioversion with dofetilide were significantly higher among patients in whom it was used as a second-line agent (53% versus 29%, p=0.026). The average duration of dofetilide therapy for patients in whom dofetilide was their first AAD was 787 days. The rate of discontinuation of dofetilide during the initial admission was 19%. Dofetilide use discordant from the 2011 MSR guidelines was high, particularly in patients for whom dofetilide was chosen as first-line AAD therapy. Dofetilide persistency appears high relative to other AADs.

KEYWORDS. Anti-arrhythmic drugs, atrial fibrillation, dofetilide, rhythm control.

The authors report no conflicts of interest for the published content.
Manuscript received May 12, 2016, Final version accepted July 6, 2016.
Address correspondence to: Michael H. Kim, MD, MMM, FACC, FHRS, Chief of Cardiology, Professor of Medicine, SIU School of Medicine, 801 N. Rutledge St, MC 9627, Springfield, IL 62702, USA. E-mail: mhkim.ep@gmail.com

Introduction

Atrial fibrillation (AF) is a highly prevalent problem in the United States, affecting about 1% of the population and about 5% of the population aged 65 years and older.¹ The deleterious health effects of AF are protean and include a marked increase in embolic stroke risk and a strong association with incident heart failure and all-cause mortality.² The scope of the problem is growing as the average age of persons in this country steadily rises: by the year 2050, an estimated 12 million Americans will have AF.³

Dofetilide is a class III anti-arrhythmic drug (AAD) that is used to restore and maintain sinus rhythm in patients with symptomatic AF. Dofetilide does not exacerbate bradycardia and has been shown to be safe for use in patients with left ventricular dysfunction.^4,5 The 2006 and 2011 Maintenance of Sinus Rhythm (MSR) guidelines list dofetilide as a first-line AAD in patients with coronary artery disease (CAD) and congestive heart failure (CHF), and it is classified as a second-line therapy in patients with structurally normal hearts, and not recommended in patients with significant left ventricular hypertrophy (LVH).⁶ Initiation of dofetilide requires hospitalization with telemetry monitoring, because the medication prolongs the QT interval and increases the risk for polymorphic ventricular tachycardia (VT). Dofetilide can only be prescribed by accredited providers. Although dofetilide is quite potent and effective (with chemical cardioversion rates exceeding 70% in some series of patients with persistent AF),⁷ there is significant cost associated with hospitalization for dofetilide initiation.⁸ There are few data describing the long-term efficacy and tolerability of dofetilide therapy.

We sought to examine patterns of dofetilide use for the treatment of AF at our institution and compare clinical use of the medication with contemporary MSR guidelines (we use the 2011 guidelines, as those were applicable during the study period; an update to the guidelines was made in 2014). Further, we sought to describe the duration of therapy and quantify the number of patients in whom the drug was discontinued before discharge from the initiation hospitalization.

Materials and methods

The data sources for this study were the Northwestern University Enterprise Data Warehouse and the electronic medical record. Patients were included in the study if they carried a diagnosis of AF and were admitted to the hospital for dofetilide initiation between January 2005 and December 2009. Patients were excluded if they were younger than 18 years at the time of admission for dofetilide initiation. All ages over 89 were reported in aggregate in order to ensure confidentiality. Follow-up data were collected during November 2012.

Eligible patients were identified via an Enterprise Data Warehouse search. Using a coded identifier list in order to protect the patient’s confidentiality, a chart review was performed. Patient characteristics, co-morbidities, and details of dofetilide use were extracted from the electronic medical record and used to populate a deidentified database. The study protocol was approved by the institutional review board.

Analysis

First, characteristics of patients (as of the date of admission for dofetilide initiation) were described. Based on those characteristics, each patient was classified according to the 2011 MSR classification, which groups patients with AF into categories on the basis of their comorbidities, including CAD, CHF, and hypertension (HTN). We have numerically annotated these MSR classifications as 0–4 (Figure 1). On the basis of whether dofetilide was used as a first-line or second-line agent, we then determined whether dofetilide was used concordant with 2011 MSR guidelines in each case.

Some drug-specific clinical outcomes were abstracted from the chart review. These included chemical cardio-version with dofetilide, rate of dofetilide discontinuation at admission, and average duration of dofetilide therapy.

Results

Overall, 122 patients were included in the study: the mean age was 62.3 ± 13.3 years, 107 (89%) patients were white, 80 (66%) were male, 40 (33%) had CHF, and 53 (43%) had HTN (Table 1).

Of the 122 patients, 80 (66%) were admitted in atrial fibrillation and 56 (46%) were antiarrhythmic drug naïve.

The tiered MSR classification was assigned numbers for each of the five categories and the number of patients in each category was tabulated (Table 2).

Based on the 2011 MSR classification and information whether dofetilide was being used as a first-line agent, the “appropriateness” of dofetilide use, as defined by concordance with the MSR classification, was quantified in this cohort (Table 3). Use of dofetilide was more often concordant with MSR guidelines when dofetilide was prescribed as a second-line anti-arrhythmic agent. Of the 36 patients with non-guideline use of dofetilide, the breakdown was as follows: 1) 15 patients where dofetilide was used as first-line drug who had structurally normal hearts and no CAD or CHF; 2) 10 patients where dofetilide was a second-line drug who had HTN and significant LVH; 3) six patients where dofetilide was a first-line drug who had HTN and significant LVH; and 4) five patients where dofetilide was a first-line drug who had HTN and no significant LVH.

Selected dofetilide-related outcomes were adjudicated. Eighty patients were admitted in AF; among those, 43% (34/80) chemically cardioverted to sinus rhythm during the dofetilide load. The rate of dofetilide discontinuation during the initial admission was 19% (23/122). The discontinuation rate of 19% was due to either QT issues (prolongation), torsades, other non-sustained VT, or inefficacy. No discontinuations were related to subjective patient complaints. The average duration of dofetilide therapy was 597 ± 780 days.

Discussion

In our cohort of patients with AF admitted to the hospital for dofetilide loading, a significant percentage of dofetilide use was discordant from 2011 MSR guidelines. The persistency rate of dofetilide (mean 597 days) was high compared with real-world use of other AADs where the median time to discontinuation was 89 days with a 76% discontinuation rate for the initial rhythm control drug.⁹ A recent retrospective analysis of amiodarone and sotalol use showed that these drugs were used in patients with different clinical characteristics, with persistency rates of only 53% for sotalol and 31% for amiodarone at one year.¹⁰

Of the patients admitted who were in AF, 43% chemically cardioverted with dofetilide. Patients in whom dofetilide was administered as a first-line agent were much more likely to be discordant with the 2011 MSR guidelines than those patients prescribed dofetilide as a second- or third-line agent.

The fact that dofetilide was being used as a first-line agent (contrary to the recommendation of the contemporary guidelines) suggests that practitioners frequently encountered clinical scenarios where dofetilide was a more appealing first-line agent than the alternatives. This may, in part, be because many patients with AF have some degree of sinus node dysfunction and baseline bradycardia: dofetilide as an agent that does not exacerbate bradycardia is an attractive agent in this situation. This may be particularly true in patients who are not candidates for class Ic agents (i.e. patients with CAD or CHF). In such patients, dofetilide may be perceived as a better tolerated and less toxic alternative to amiodarone, particularly in younger patients who can be expected to accumulate a risk of amiodarone-induced organ toxicity over a longer period of therapy. In addition, over the time period of data collection, rhythm control and catheter ablation of AF have become increasingly more common as an AF treatment strategy. Accordingly, the perception of more successful maintenance of sinus rhythm with dofetilide and the avoidance of amiodarone may have played a role in its first-line utilization.

Interestingly, subsequent to the collection of these data, the 2014 MSR guidelines have recategorized dofetilide as a first-line agent in all subsets of patients with AF (no structural heart disease, CAD, CHF).¹¹ This is somewhat unusual, as the guidelines cite data from a decade ago as the rationale for the change to the 2011 MSR guidelines. About 20% of patients had the drug discontinued during the index hospitalization because of excessive QT prolongation or ventricular arrhythmia. Typical QTc interval criteria for dose reduction or discontinuation of dofetilide are an increase of more than 15% from baseline or an increase to over 500 ms in the absence of bundle branch block or a paced QRS complex. Ultimately, drug discontinuation was completely at the discretion of the treating physician.

The main limitations for this study are the retrospective nature of the analysis, relatively small cohort size, and the fact that it represents a single-center experience. The exact reasons for the discordant use of dofetilide could not be fully categorized. Practices observed at other institutions and the growing use of dofetilide nationally suggest that this pattern of use is present in other centers. The small number of outcomes precluded the use of multivariate analysis to identify predictors of those outcomes (such as chemical cardioversion, dofetilide discontinuation at first admit, etc.).

Conclusions

Dofetilide is a potent and effective AAD. The two main findings of this investigation were the frequent use of dofetilide as a first-line agent discordant from prior AF guidelines and prior to the publication of the current guidelines, and the high persistency rate among patients who initially tolerated the medication. Although its use is challenging and expensive and there is a relatively high rate of early discontinuation, the increased persistency rate on therapy may impact the outcomes and quality of AF disease management. With the recategorization of dofetilide as a first-line agent in the 2014 MSR guidelines, it would be expected that dofetilide use will correspondingly increase.

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