What are the guidelines for initiating Tikosyn (dofetilide) treatment in patients with atrial fibrillation or atrial flutter?

Guidelines for Initiating Tikosyn (Dofetilide) Treatment in Patients with Atrial Fibrillation or Atrial Flutter

Tikosyn (dofetilide) must be initiated in a hospital setting with continuous ECG monitoring for a minimum of 3 days, with patients not being discharged within 12 hours of conversion to normal sinus rhythm. 1

Initial Assessment and Preparation

• Dofetilide is a Class III antiarrhythmic drug that is FDA-approved for the conversion of atrial fibrillation/flutter and maintenance of sinus rhythm 2
• Before initiating treatment, the following baseline assessments must be completed:
  • 12-lead ECG to determine baseline QTc interval 1, 3
  • Serum potassium and magnesium levels 3, 1
  • Serum creatinine for estimation of creatinine clearance 1, 3
• Contraindications to dofetilide initiation include:
  • QTc interval >440 msec (or >500 msec in patients with ventricular conduction abnormalities) 1
  • Creatinine clearance <20 mL/min 1
  • Hypokalemia or hypomagnesemia (must be corrected before initiation) 1

Dosing Algorithm

The dosing of dofetilide must be individualized according to creatinine clearance and QTc interval 1:

1. Calculate creatinine clearance using the Cockcroft-Gault formula:

   • For males: (140-age) × weight(kg) ÷ (72 × serum creatinine in mg/dL)
   • For females: (140-age) × weight(kg) × 0.85 ÷ (72 × serum creatinine in mg/dL) 1

2. Determine starting dose based on creatinine clearance:

   • 60 mL/min: 500 mcg twice daily

   • 40-60 mL/min: 250 mcg twice daily
   • 20-<40 mL/min: 125 mcg twice daily
   • <20 mL/min: Dofetilide is contraindicated 1

3. Monitor QTc interval 2-3 hours after the first dose:

   • If QTc increases by >15% from baseline or exceeds 500 msec (550 msec with ventricular conduction abnormalities), dose reduction is required 1
   • Dose adjustment based on QTc prolongation:
     • If starting dose was 500 mcg BID → reduce to 250 mcg BID
     • If starting dose was 250 mcg BID → reduce to 125 mcg BID
     • If starting dose was 125 mcg BID → reduce to 125 mcg once daily 1

4. Continue monitoring QTc 2-3 hours after each subsequent dose during hospitalization 1

Monitoring Requirements

• In-hospital monitoring:

  • Continuous ECG monitoring for a minimum of 3 days 1, 3
  • Monitoring for at least 12 hours after electrical or pharmacological conversion to sinus rhythm 1
  • QTc assessment 2-3 hours after each dose 1
  • Daily assessment of renal function and electrolytes 1, 3

• Long-term monitoring:

  • Renal function and QTc should be re-evaluated every 3 months or as medically warranted 1
  • More frequent monitoring is needed for patients taking other QT-prolonging drugs or with changing kidney function 3
  • Serum potassium and magnesium should be maintained within normal range 1

Efficacy and Safety Considerations

• Dofetilide is effective for both conversion to sinus rhythm and maintenance of sinus rhythm:

  • Conversion rates of 30% have been reported in clinical trials 4
  • Real-world conversion rates may be higher than those reported in clinical trials 5
  • Median time to relapse after conversion exceeds one year 4

• Major safety concern: Risk of torsades de pointes

  • Incidence ranges from 0.3-10.5% of patients and is dose-related 2, 6
  • Most proarrhythmic events occur within the first 3 days of treatment 2
  • This risk necessitates the mandatory in-hospital initiation 1, 2

• Dofetilide has demonstrated neutral effects on mortality in patients with heart failure and post-myocardial infarction, making it one of the few antiarrhythmic drugs (along with amiodarone) with proven safety in these high-risk populations 4, 5

Drug Interactions

• Concomitant use with drugs that prolong the QT interval should be avoided 1
• Drugs that interfere with renal elimination or metabolism of dofetilide must be avoided 4
• Dofetilide can be safely co-administered with digoxin and beta-blockers 4
• Dofetilide should not be initiated out of hospital (Class III: Harm recommendation) 3

Clinical Pearls and Pitfalls

• Patients must have an adequate supply of dofetilide at their individualized dose upon discharge to allow uninterrupted dosing 1
• Dofetilide is particularly useful when atrioventricular nodal blockade needs to be avoided 5
• If at any time after the second dose the QTc exceeds 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued 1
• Patients should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion 1