How should dofetilide be initiated, dosed according to creatinine clearance, and monitored (including corrected QT interval) for atrial fibrillation or atrial flutter, and what are its contraindications and alternative rhythm‑control options?

Dofetilide Initiation, Dosing, and Monitoring for Atrial Fibrillation/Flutter

Dofetilide must be initiated exclusively in a hospital setting with mandatory 3-day continuous ECG monitoring, with dosing strictly adjusted according to creatinine clearance and QTc interval measurements taken 2-3 hours after each of the first 5 doses. 1, 2

Mandatory Inpatient Initiation Requirements

Dofetilide should never be initiated out of hospital (Class III: Harm recommendation). 1

Required Monitoring Protocol

• Minimum 3-day hospitalization with continuous telemetry monitoring 2, 3, 4
• QTc measurement 2-3 hours after each of the first 5 doses 2
• Baseline creatinine clearance calculation before first dose 1, 3
• Cardiac resuscitation capabilities must be immediately available 3, 4
• Serum electrolyte monitoring (potassium and magnesium) 3

Creatinine Clearance-Based Dosing

The dose must be adjusted according to calculated creatinine clearance as follows: 1

Creatinine Clearance (mL/min)	Dofetilide Dose
>60	500 mcg twice daily
40-60	250 mcg twice daily
20-40	125 mcg twice daily
<20	Contraindicated

QTc-Based Dose Adjustments and Discontinuation

If QTc exceeds specific thresholds at any monitoring point, immediate action is required: 1, 3

• If QTc >500 msec (or >550 msec with ventricular conduction abnormalities) at any time during the first 5 doses: reduce dose by 50% 1
• If QTc remains >500 msec after dose reduction: discontinue dofetilide 1
• The QTc prolongation is dose-dependent and represents the mechanism for both efficacy and the primary safety concern 3, 4

Absolute Contraindications

Dofetilide is contraindicated in the following conditions: 1, 3

• Creatinine clearance <20 mL/min 1
• Baseline QTc >440 msec (or >500 msec with bundle branch block) 3
• Hypokalemia or hypomagnesemia 1, 3
• Concomitant use of drugs that prolong QT interval 3
• Concurrent use of verapamil, cimetidine, trimethoprim, ketoconazole, prochlorperazine, or megestrol (interfere with renal elimination) 5

Clinical Efficacy and Timing

Most conversions to sinus rhythm occur within 24-36 hours of initiating therapy, with 87% converting within 30 hours. 2, 3, 4

• Dofetilide achieved 32% conversion rate versus 1% with placebo after 3 days 2
• For atrial flutter specifically, dofetilide demonstrated 70% conversion rate versus 9% with flecainide 3, 4
• Real-world acute conversion rates are higher than those reported in clinical trials 6

Torsades de Pointes Risk

The risk of torsades de pointes is 0.8-3.3%, with 76% of episodes occurring in the first 3 days. 2

This risk is dose-related and ranges from 0.3-10.5% across studies, which is why the mandatory 3-day monitoring period is critical. 3, 4, 7 Risk factors for torsades include heart failure, left ventricular hypertrophy, bradycardia, and female gender. 7

Preferred Patient Populations

Dofetilide and amiodarone are the only antiarrhythmics proven safe in heart failure patients with ejection fraction ≤35%, as demonstrated in the DIAMOND trials. 2

• First-line agent in heart failure patients (along with amiodarone) due to proven safety in this population 2
• Second-line agent in coronary artery disease after beta-blockers and sotalol 2
• Well-tolerated in patients with acceptable renal function and normal QT interval, especially when AV nodal blockade needs to be avoided 6

Alternative Rhythm-Control Options

When dofetilide is contraindicated or fails, alternative antiarrhythmic drugs include: 1

For patients without structural heart disease:

• Flecainide (150-300 mg every 8-12 hours) 1
• Propafenone (150-300 mg every 8 hours) 1
• Sotalol 1

Critical caveat: Flecainide and propafenone must be given with beta blockers or calcium channel blockers administered ≥30 minutes before the Class IC agent to prevent 1:1 AV conduction during atrial flutter. 1

For patients with heart failure or significant structural heart disease:

• Amiodarone (only alternative with proven safety in this population) 1, 2

For patients with hypertension and substantial left ventricular hypertrophy:

• Amiodarone 1
• Catheter ablation 1

For atrial flutter specifically:

• Catheter ablation of the cavotricuspid isthmus (CTI) is highly effective and reasonable as first-line therapy for symptomatic CTI-dependent atrial flutter 1

Ongoing Monitoring After Hospital Discharge

• Renal function monitoring is essential as approximately 80% of dofetilide is renally excreted 3, 4
• Dose adjustment required if creatinine clearance changes 1, 3
• Avoid drugs that interfere with renal elimination or metabolism 5
• Can be co-administered with digoxin and beta-blockers 5

Key Clinical Pitfalls to Avoid

• Never initiate dofetilide outpatient - this is a Class III: Harm recommendation 1
• Never use in patients with creatinine clearance <20 mL/min 1
• Never skip QTc measurements at 2-3 hours post-dose during the first 5 doses 2
• Never use Class IC agents (flecainide/propafenone) without prior AV nodal blockade to prevent rapid ventricular response during atrial flutter 1
• Never overlook electrolyte abnormalities before initiation 1, 3