Author: Zachary R. Noel, PharmD, BCPS

For patients with atrial fibrillation and structural heart disease (defined as prior myocardial infarction, heart failure, or left ventricular hypertrophy for purposes of this blog), options in the armamentarium of antiarrhythmic drugs (AADs) are curtailed due to the proarrhythmic risks and negative inotropic effects of many AADs (e.g., Class IA and IC antiarrhythmics). Sotalol, amiodarone, and dofetilide remain the most commonly relied upon drugs for these patients. Of these AADs, amiodarone has been the cornerstone due to its low proarrhythmic risk. While the risk of arrhythmia associated with amiodarone is low, the risk of significant long term adverse effects (e.g., pulmonary fibrosis, thyroid dysfunction, hepatotoxicity) is 15% after one year and up to 50% with chronic use beyond one year.1

Dofetilide is a Vaughan-Williams Class III AAD that, unlike other oral Class III AADs, selectively inhibits the cardiac delayed rectifier potassium current (Ikr). Although it is effective at both converting and maintaining sinus rhythm and is void of extracardiac adverse effects, dofetilide has largely been utilized as a second or third line AAD because of the risk of Torsades de Pointes (TdP). Early clinical trials suggested the risk of TdP was as high as 3.3%; however, more recent observational analyses suggest a rate of 0.8-1.2%.2, 3 This blog will briefly review dofetilide’s safety and efficacy compared to other antiarrhythmic drugs and highlight clinical pearls for its use.

Did You Know?
The U.S. Food and Drug Administration Risk Evaluation and Mitigation Strategy (REMS) for dofetilide was terminated in 2016. Providers and pharmacies no longer have to be authorized to prescribe/dispense dofetilide

Comparative Effectiveness of Dofetilide

Dofetilide has been studied for pharmacologic cardioversion of atrial flutter (AFL) and atrial fibrillation (AF) as well as long term maintenance of normal sinus rhythm.4 Dofetilide is successful in converting patients to normal sinus rhythm (NSR) within 72 hours of initiation ~30% of the time and maintains NSR in 60% of patients at one year. While these percentages seem suboptimal, they are comparable or better than other oral agents used in structural heart disease (Table 1). In comparison, amiodarone is 27% effective at converting patients to NSR over the course of 3-4 weeks and maintains NSR in ~65% of patients at one year.5 Sotalol, although comparable to amiodarone and dofetilide with regards to pharmacologic cardioversion, is only ~45% effective at maintaining NSR at one year.5

 

TABLE 1: Effectiveness of Oral Antiarrhythmic Drugs in Structural Heart Disease1-5

Antiarrhythmic Drug Successful Pharmacologic Cardioversion (%) Maintenance of Normal Sinus Rhythm at 1 Year (%) Adverse Effects (%)
Dofetilide* 30 60 Torsade de pointes (1%)
Amiodarone** 27 65 Pulmonary toxicity (2%)
Hepatotoxicity (<3%)
Hypothyroidism (up to 22%)
Hyperthyroidism (up to 12%)
Photosensitivity (up to 75%)
Ocular adverse effects (90%)
Sotalol 24 45 Bradycardia (15%)
Exacerbation of heart failure (5%)
Torsades de pointes (0.5%)

*Effectiveness is dose-dependent. Listed rates are with 500 mcg bid doses.
**Rates of adverse effects are dose-dependent and increase with cumulative exposure.

 

Adverse Effects of Dofetilide

As mentioned previously, rates of TdP with dofetilide in early clinical trials were as high as 3%. However, observational trials have demonstrated rates closer to 1% when used for supraventricular arrhythmias.2,6 Upwards of 75% of reported TdP events occur within the first 3 days of initiation of dofetilide, hence patients are required to undergo continuous cardiac monitoring for 3 days when starting dofetilide. Once outside of this window, rates of TdP and sudden cardiac death from arrhythmias remain quite low (0.05%).7 Dofetilide does not exhibit negative inotropic or chronotropic effects and is void of extracardiac adverse effects.

In comparison to dofetilide, sotalol and amiodarone have much higher rates of adverse effects (Table 1). Sotalol carries a 15% risk of bradycardia and has a risk of TdP only slightly lower than that of dofetilide.  In addition, the negative inotropic effects of sotalol make it less favorable in patients with heart failure, particularly those with severe left ventricular dysfunction (e.g., left ventricular ejection fraction ≤ 20%). Amiodarone is fraught with toxicity when taken chronically and requires close long-term monitoring, including annual eye exams, frequent thyroid function testing, liver function testing, and an annual chest X-ray to monitor for pulmonary fibrosis.

 

Did You Know?
An EKG should be obtained at baseline and 2-3 hours after each dose of dofetilide during initiation.

QTc standardizes the QT interval based on heart rate. Patients with a QTc > 440 msec should not be started on dofetilide (unless a ventricular conduction abnormality is present).

The Bazett’s formula is most commonly used to calculate QTc and is most accurate when heart rates are between 60 – 100 bpm.

Patients in atrial fibrillation have beat-to-beat variability in their QT (and QTc) interval. In these patients, it’s important to take multiple QTc measurements and average them, rather than using an isolated measurement.

 

Clinical Pearls for Using Dofetilide

  • Heart Failure – Dofetilide was studied in patients with atrial fibrillation and left ventricular dysfunction in the DIAMOND-CHF trial (Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction).6 Although there was no difference in mortality among those treated with dofetilide compared to those treated with placebo, there was a significant reduction in hospitalizations for worsening heart failure in patients with atrial fibrillation at baseline (HR 0.64; 95% CI 0.46-0.91), likely owing to the greater percentage of patients remaining in normal sinus rhythm (HR 0.35; 95% CI 0.22-0.57). While amiodarone and sotalol can also be considered in patients with heart failure, the toxicities of amiodarone and negative inotropic effects of sotalol can be prohibitive. Added caution should be taken in patients with concomitant chronic kidney disease, and patients on loop diuretics should have their magnesium and potassium repleted.
  • Drug Interactions – Dofetilide is renally eliminated via active tubular secretion by organic cation transporters (OCTs). Inhibitors of OCT, such as hydrochlorothiazide, verapamil, and trimethoprim, are an absolute contraindication with dofetilide because they inhibit tubular secretion and thus increase serum concentrations of dofetilide. Other substrates for tubular cation transporters (e.g., metformin, selective serotonin reuptake inhibitors) may only modestly impact dofetilide concentrations. If used concomitantly, these therapies should be administered together upon dofetilide initiation so that changes in QTc can be accounted for while the patient is under continuous cardiac monitoring. Dofetilide is only minimally metabolized by CYP 3A4, and thus minimally affected by CYP 3A4 inhibitors.
  • Renal dysfunction – Dofetilide is eliminated 80% as unchanged drug in the urine. As such, patients with chronic kidney disease should be closely monitored. The starting dose is 250 mcg and 125 mcg for patients with a creatinine clearance (as measured by Cockcroft-Gault) of 40-60 ml/min and 20-40 ml/min, respectively.
  • Ventricular Conduction Abnormality – The standard QTc cutoff for dofetilide initiation is 440 msec; however, in patients with a ventricular conduction abnormality (e.g., bundle branch block), the cutoff is 500 msec. In these patients, if at any point the QTc extends to >550 msec, dofetilide should be discontinued.

Conclusion

Dofetilide is an effective and often underutilized AAD in patients seeking rhythm control of atrial fibrillation with concomitant structural heart disease. The risk of TdP is greatest within the first 72 hours of starting dofetilide and requires close inpatient monitoring upon initiation, thorough evaluation for drug interactions, and routine monitoring of renal function; however, long-term dofetilide use is better tolerated than other AADs such as amiodarone and sotalol.

 

Zachary R. Noel, PharmD, BCPS

Dr. Noel is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in cardiology at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @ZacNoelCardsRx.

 

References:

  1. Goldschlager N, Epstein A, Murphy E, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm [serial online]. September 2007;4(9):1250-1259. Available from: MEDLINE, Ipswich, MA. Accessed February 20, 2018.
  2. Abraham J, Saliba W, Wilkoff B, et al. Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circulation. Arrhythmia And Electrophysiology [serial online]. August 2015;8(4):772-776. Available from: MEDLINE, Ipswich, MA. Accessed February 12, 2018.
  3. Pedersen O, Bagger H, Keller N, Marchant B, Køber L, Torp-Pedersen C. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation [serial online]. July 17, 2001;104(3):292-296. Available from: MEDLINE, Ipswich, MA. Accessed February 13, 2018.
  4. Singh S, Zoble R, Billing C, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation [serial online]. November 7, 2000;102(19):2385-2390. Available from: MEDLINE, Ipswich, MA. Accessed February 13, 2018.
  5. Singh BN, Singh SN, Reda DJ, Tang XC, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005;352:1861–1872.
  6. Torp-Pedersen C, Møller M, Camm A, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. The New England Journal Of Medicine [serial online]. September 16, 1999;341(12):857-865. Available from: MEDLINE, Ipswich, MA. Accessed February 12, 2018.
  7. Abhishek J, Seth G. Dofetilide induced torsade de pointes: Mechanism, risk factors and management strategies. Indian Heart Journal, Vol 66, Iss 6, Pp 640-648 (2014) [serial online]. 2014;(6):640. Available from: Directory of Open Access Journals, Ipswich, MA. Accessed February 20, 2018.
Dofetilide: A Diamond in the Rough for Atrial Fibrillation in Patients with Structural Heart Disease
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