Dofetilide
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Conversion of atrial fibrillation/atrial flutter to normal sinus rhythm | Adults with highly symptomatic AF/AFL of >1 week duration | Pharmacologic cardioversion | FDA Approved |
| Maintenance of normal sinus rhythm after conversion of AF/AFL of >1 week duration | Adults with highly symptomatic AF/AFL who have been converted to NSR | Chronic monotherapy | FDA Approved |
Dofetilide is a selective blocker of the rapidly activating delayed rectifier potassium current (IKr). It is one of the few oral antiarrhythmics that can be used in patients with structural heart disease, including reduced left ventricular ejection fraction, because the DIAMOND-CHF and DIAMOND-MI mortality studies showed that dofetilide is mortality-neutral in heart failure and post-MI populations. This distinguishes it from Class IC agents (flecainide, propafenone), which increase mortality in these settings. The 2023 ACC/AHA/ACCP/HRS atrial fibrillation guideline lists dofetilide as one option for rhythm control in patients with structural heart disease where Class IC agents are unsafe.
Two important boundaries on the FDA-approved indication should be noted explicitly: dofetilide is approved only for AF/AFL of greater than one week duration, and the prescribing information states that dofetilide has not been shown to be effective in patients with paroxysmal atrial fibrillation. Because of its torsades risk, dofetilide must be initiated in a hospital setting with at least three days of continuous ECG monitoring per the boxed warning, even though the FDA-mandated REMS program for the brand-name product was rescinded in 2016.
Maintenance of sinus rhythm in paroxysmal AF (low-quality evidence): the FDA prescribing information explicitly states dofetilide has not been shown to be effective in paroxysmal AF; observational data suggest substantially lower long-term success rates compared with persistent AF, and proarrhythmia risk persists. Reserved for patients who have failed multiple alternative agents.
Suppression of recurrent atrial tachycardia (low-quality evidence): occasionally used in specialized electrophysiology practice when other agents have failed.
Bridging in patients awaiting catheter ablation (moderate-quality evidence): observational cohorts have reported acceptable safety and partial symptomatic benefit when used as a second-line agent in patients refractory to other antiarrhythmics.
Ventricular arrhythmias (low-quality evidence): limited published experience; not a recommended first-line indication.
Dosing
Dofetilide is unique among commonly prescribed antiarrhythmics in that the dose must be selected from a matrix of two variables — calculated creatinine clearance (Cockcroft–Gault using actual body weight) and corrected QT interval — and re-checked at every dose for the first three days of therapy. The doses below organize the regimen by clinical scenario rather than by capsule strength.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Atrial fibrillation/flutter — inpatient initiation, CrCl >60 mL/min | 500 mcg PO BID | 500 mcg BID, modified by post-dose QTc | 500 mcg BID | Recheck QTc 2–3 h after each dose for the first 5 doses; halve dose if QTc rises >15% above baseline OR >500 ms after dose 1. Discontinue if QTc >500 ms (550 ms with VCA) after the second dose or any subsequent dose. |
| CrCl 40–60 mL/min | 250 mcg PO BID | 250 mcg BID, modified by post-dose QTc | 250 mcg BID | Halve to 125 mcg BID if early QTc criteria met after dose 1. Recheck CrCl every 3 months as outpatient. |
| CrCl 20–39 mL/min | 125 mcg PO BID | 125 mcg BID, modified by post-dose QTc | 125 mcg BID | If QTc criteria met after first dose, reduce to 125 mcg once daily. High-vigilance group — consider alternative antiarrhythmic. |
| CrCl <20 mL/min | Contraindicated — do not initiate | Hemodialysis effect on dofetilide is unknown. Same prohibition applies if CrCl declines below 20 mL/min during therapy. | ||
| Reinitiation after a treatment gap | Same starting dose as initial CrCl/QTc-based regimen | Per QTc response over the inpatient course | 500 mcg BID | Hospital readmission for monitoring is required even when restarting at a previously tolerated dose. Reload data show TdP risk is higher when reloading at a higher than previously tolerated dose. |
QTc-Based Dose Adjustment During Initiation
| Trigger (after dose 1, before dose 2) | Action | Trigger (after dose 2 or any later dose) | Action |
|---|---|---|---|
| QTc rises >15% above baseline OR QTc >500 ms (550 ms with VCA) | Halve the next dose: 500 mcg → 250 mcg BID 250 mcg → 125 mcg BID 125 mcg → 125 mcg once daily | QTc >500 ms (550 ms with VCA) | Discontinue dofetilide and observe until QTc returns to baseline. |
Population-Specific Adjustments
| Population | Adjustment | Rationale |
|---|---|---|
| Older adults | Initiate at the lower end of the matrix; verify CrCl using actual body weight | Age-related decline in renal function may not be reflected in serum creatinine alone; risk of TdP rises with female sex and advanced age. |
| Female patients | No formal dose change; heightened TdP vigilance | Female sex was an independent risk factor for TdP in DIAMOND-CHF analyses (odds ratio approximately 3). |
| NYHA III–IV heart failure | No formal dose change; heightened TdP vigilance | NYHA III–IV class was an independent TdP risk factor in DIAMOND-CHF analyses (odds ratio approximately 4). |
| Hepatic impairment | Mild–moderate: no adjustment. Severe: limited data; use cautiously | Hepatic metabolism contributes minimally; PK is not significantly altered in mild–moderate dysfunction. |
| Pediatric (<18 y) | Safety and efficacy not established | Excluded from pivotal trials. |
The boxed-warning protocol — baseline ECG and CrCl, dosing matrix, QTc check at 2–3 hours after each of the first five doses, dose halving for early QTc rise, discontinuation for sustained QTc >500 ms after dose 2, and three full days of telemetry — is what makes dofetilide safe enough to use. Outside this structure, the drug carries a torsades risk substantially higher than other Class III agents. Most TdP events occur within the first 72 hours, which is exactly when the patient is on telemetry; this design intentionally surfaces the risk where it can be managed.
Pharmacology
Mechanism of Action
Dofetilide is a methanesulfonamide derivative that selectively blocks the rapidly activating component of the delayed rectifier potassium current (IKr) without affecting other ion channels at therapeutic concentrations. Per the FDA prescribing information, dofetilide blocks only IKr at concentrations covering several orders of magnitude, with no relevant effect on other repolarizing potassium currents (IKs, IK1), sodium channels, or alpha- or beta-adrenergic receptors. This action prolongs the cardiac action potential duration and effective refractory period in both atrial and ventricular myocardium, terminating reentry circuits responsible for atrial fibrillation and atrial flutter. Unlike amiodarone or sotalol, dofetilide has no clinically meaningful effect on heart rate, blood pressure, AV nodal conduction, or cardiac contractility, and lacks beta-adrenergic blocking activity. This selectivity allows safer use in patients with sinus node disease, AV block, hypotension, or systolic dysfunction — but it also means dofetilide does not slow the ventricular response in atrial fibrillation and may be used together with rate-controlling agents.
The drug exhibits “reverse use-dependence” — QT prolongation is greatest at slow heart rates and after conversion to sinus rhythm, which explains why torsades de pointes most often appears shortly after restoration of sinus rhythm rather than during the initial atrial fibrillation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability >90%; Tmax 2–3 h fasted; food and antacids do not affect total exposure | May be administered without regard to meals; rapid absorption explains the timing of post-dose QTc checks at 2–3 hours. |
| Distribution | Vd ~3 L/kg (per FDA label); protein binding 60–70%, independent of plasma concentration and renal function | Modest tissue distribution and stable protein binding mean dofetilide does not accumulate in fat or organs the way amiodarone does. |
| Metabolism | Minor hepatic metabolism via CYP3A4 (low affinity), N-dealkylation, and N-oxidation; no quantifiable circulating metabolites | Strong CYP3A4 inhibitors (e.g., ketoconazole) can raise levels and trigger TdP; dofetilide does not inhibit CYP enzymes itself. |
| Elimination | ~80% renal excretion (~80% as unchanged drug); cleared by glomerular filtration plus active tubular secretion via the cation transport system; terminal half-life ~10 h | Renal-dose adjustment is mandatory and contraindicated below CrCl 20 mL/min. Drugs that inhibit organic cation transport (cimetidine, trimethoprim, ketoconazole, megestrol, prochlorperazine, dolutegravir) are contraindicated. |
Side Effects
Dofetilide is generally well tolerated, with a non-cardiac adverse-event profile dominated by mild, self-limited symptoms. The dominant safety signal is torsades de pointes, which is dose-dependent and almost always emerges during the first 72 hours of therapy under telemetry — the rationale for the inpatient initiation protocol. Incidence rates below are drawn primarily from the supraventricular arrhythmia trials in the Tikosyn FDA label and from the DIAMOND mortality studies, with the source population indicated where rates differ meaningfully between settings.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | ~11% | Most frequently reported adverse event in pivotal trials; usually mild and self-limited. |
| Chest pain | ~10% | Often non-cardiac; investigate for ischemia or arrhythmia recurrence first. |
| Ventricular arrhythmias (DIAMOND population — heart failure / post-MI) | Up to ~14.5% | Higher rate reflects the high baseline arrhythmia burden in patients with structural heart disease enrolled in DIAMOND, not the rate expected in the SVT/AF population. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | ~8% | Distinguish orthostatic light-headedness from arrhythmia-related presyncope. |
| Respiratory tract infection | ~7% | Rate similar to placebo; no mechanistic link to dofetilide. |
| Dyspnea | ~6% | Often related to underlying heart failure; reassess for decompensation. |
| Nausea | ~5% | Usually mild; rarely requires intervention. |
| Insomnia | ~4% | Reported numerically more often than placebo. |
| Flu syndrome / asthenia | ~4% | Generally mild and not therapy-limiting. |
| Diarrhea, back pain, abdominal pain, rash | ~3% each | Rates similar to placebo for several of these. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Torsades de pointes — supraventricular arrhythmia population (FDA label) | 0.8% (with recommended renal-adjusted dosing) | Majority within first 3 days | IV magnesium sulfate, correct electrolytes, withhold drug, pace if bradycardic; permanent discontinuation usually required. |
| Torsades de pointes — heart failure (DIAMOND-CHF) | 3.3% (25/762 patients) | Most within first 3 days | As above; female sex and NYHA III–IV are independent risk factors. |
| Torsades de pointes — post-MI (DIAMOND-MI, with renal-adjusted dose) | ~0.9% (per Jaiswal 2014 review of DIAMOND data) | Most within first 3 days | Correct electrolytes; verify CrCl and concomitant medications. |
| Sustained ventricular tachycardia | ~2.0% (FDA label, SVT studies) | Days to weeks | Most common cause for trial discontinuation; manage per ACLS. |
| Sudden cardiac death | Rare in published series | Any time | Outpatient deaths reported when protocol breaches occur (drug interactions, electrolyte loss, missed CrCl re-check). |
| QTc prolongation requiring intervention | Approximately 23% of patients required dose reduction for renal function during initiation; ~3% required additional reduction or discontinuation for excessive QT/QTc prolongation (FDA label, SAFIRE-D and EMERALD) | Within 2–3 h of any dose | Halve dose if criteria met after dose 1; discontinue if criteria met after dose 2 or any later dose. |
| Stroke / cerebral ischemia | Reported, frequency not quantified in label | Variable | Confirm therapeutic anticoagulation before electrical or pharmacologic cardioversion. |
| Reason for Discontinuation | Approx. Incidence | Context |
|---|---|---|
| Ventricular tachycardia (sustained or non-sustained) | 2.0% | Most common reason for trial discontinuation per FDA label. |
| Excessive QTc prolongation during initiation | ~3% require down-titration or discontinuation in pivotal trials; ~30% require dose adjustment in reload admissions | Most occur after dose 1 or 2. |
| Symptomatic non-cardiac adverse effects | <2% | Most non-cardiac adverse events do not require discontinuation. |
| Decline in renal function below CrCl 20 mL/min | Population-dependent | Discontinue if CrCl falls below contraindication threshold during therapy. |
Acute management is identical regardless of the triggering antiarrhythmic: discontinue dofetilide immediately, give intravenous magnesium sulfate 1–2 g (regardless of measured serum magnesium), correct hypokalemia aggressively to a target potassium ≥4 mEq/L, and consider isoproterenol or transvenous pacing for bradycardia-dependent TdP. Defibrillation is required for hemodynamic collapse. Investigate every modifiable contributor — concomitant QT-prolonging drug, missed CrCl re-check, hypomagnesemia, recent diuretic dose, or breach of the contraindicated drug list — before any consideration of restarting therapy.
Drug Interactions
Dofetilide has the most extensive list of contraindicated drug combinations of any oral antiarrhythmic. Two pharmacokinetic mechanisms drive nearly every major interaction: inhibition of the renal organic cation transport system, which delays dofetilide elimination, and CYP3A4 inhibition, which raises plasma exposure modestly. Either pathway can push QTc into the danger zone. Concurrent use of any QT-prolonging drug additionally raises the risk of torsades through pharmacodynamic addition. Medication reconciliation before admission for dofetilide initiation is therefore as important as the ECG and CrCl checks.
Monitoring
Monitoring during the inpatient initiation period is intensive — every dose, every two to three hours, on telemetry. After discharge, monitoring shifts to a quarterly check of renal function and ECG with prompt re-evaluation whenever clinical context changes (intercurrent illness, new medications, electrolyte loss).
-
Continuous telemetry
Minimum 3 days at initiation; or 12 h after conversion to NSR (whichever is longer)
Routine Required by the boxed warning regardless of indication; same requirement applies to reinitiation. Most TdP events occur during this window. -
12-lead ECG (QTc)
Baseline; 2–3 h after each of the first 5 doses; then every 3 months as outpatient
Routine QTc >440 ms (or >500 ms with VCA) at baseline contraindicates initiation. After dose 1, halve dose if QTc rises >15% above baseline OR exceeds 500 ms. After dose 2 or any later dose, QTc >500 ms (or >550 ms with VCA) requires discontinuation. -
CrCl (Cockcroft–Gault, actual body weight)
Baseline, then every 3 months
Routine Recalculate any time renal function may have changed (intercurrent illness, dehydration, new nephrotoxic drug). Reduce dose or stop if CrCl crosses a threshold. -
Serum potassium and magnesium
Baseline, before each dose during initiation, then periodically
Routine Maintain potassium within normal range (FDA label notes potassium levels were generally maintained above 3.6–4.0 mEq/L in clinical trials) and magnesium within normal range throughout therapy. Replete and recheck before any dose is given if values fall below target. -
Heart rate / rhythm
Continuous during initiation; periodic outpatient
Routine Heart rate <50 bpm has not been studied; use uncorrected QT (not QTc) when heart rate is <60 bpm. -
Anticoagulation status
Before any cardioversion attempt
Routine Patients with AF should be anticoagulated according to standard practice (CHA₂DS₂-VASc, prior TEE or therapeutic anticoagulation per current guideline) prior to electrical or pharmacologic cardioversion. -
Medication reconciliation
Before every dose during initiation; at every outpatient visit
Trigger-based Verify absence of contraindicated drugs and any new QT-prolonging agent. The contraindicated list includes cimetidine, dolutegravir, hydrochlorothiazide, ketoconazole, megestrol, prochlorperazine, trimethoprim, and verapamil. -
Symptom assessment
Each visit
Routine Ask about palpitations, syncope, presyncope, chest pain, and new-onset diarrhea, vomiting, or excess sweating (electrolyte loss).
12-lead ECG with QTc; serum creatinine and electrolytes; medication reconciliation against the contraindicated list; symptom-focused review for syncope, palpitations, and gastrointestinal losses; review of all new prescriptions and over-the-counter products since the last visit. Discontinue dofetilide and refer back to telemetry if QTc exceeds 500 ms (or 550 ms with VCA), if CrCl falls below 20 mL/min, or if any contraindicated drug has been started.
Contraindications & Cautions
To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see the prescribing information.
The risk of torsades de pointes is dose-related and is highest in the first 72 hours after initiation. Although the formal Risk Evaluation and Mitigation Strategy (REMS) program for Tikosyn was rescinded by the FDA in January 2016, the inpatient initiation requirement remains in the prescribing information and is the standard of care.
Absolute Contraindications
- Congenital or acquired long QT syndrome
- Baseline QT or QTc >440 ms (or >500 ms in patients with ventricular conduction abnormalities)
- Severe renal impairment — calculated CrCl <20 mL/min
- Concomitant cation transport inhibitors: cimetidine, dolutegravir, hydrochlorothiazide (alone or in any combination), ketoconazole, megestrol, prochlorperazine, trimethoprim (alone or with sulfamethoxazole), verapamil
- Known hypersensitivity to dofetilide or any component
Relative Contraindications (Specialist Input Recommended)
- Heart rate <50 beats per minute at baseline — not studied in clinical trials; consider pacemaker support
- NYHA class III–IV heart failure with female sex — independent risk factors for TdP in DIAMOND-CHF; specialist co-management advised
- Severe hepatic impairment (Child-Pugh C) — limited PK data; cautious use only
- Concurrent QT-prolonging drugs that cannot be stopped — joint cardiology and prescribing-specialty decision; sustained telemetry required
- Pregnancy — animal studies show teratogenicity; use only when potential benefit clearly outweighs fetal risk in the absence of safer alternatives
Use with Caution
- Older adults — confirm CrCl is calculated using actual body weight; age-related decline in renal function may not be reflected in serum creatinine
- Female sex — heightened TdP vigilance even within the standard dosing matrix
- Concurrent CYP3A4 inhibitors — modest pharmacokinetic interaction can be clinically meaningful
- Concurrent loop diuretics — proactively maintain potassium ≥4 mEq/L and magnesium within normal range
- Lactation — dofetilide excretion in human milk is unknown; not recommended
- Pediatric patients — safety and efficacy not established
- Paroxysmal atrial fibrillation — FDA prescribing information notes dofetilide has not been shown to be effective in paroxysmal AF; observational data show lower long-term success rates
Patient Counselling
Purpose of Therapy
Explain that dofetilide is used to convert atrial fibrillation or atrial flutter to a normal heart rhythm and to keep it normal once converted. Frame it as an effective option that requires careful initial monitoring: the first three days in hospital are essential for establishing the safe dose and identifying the small minority of patients who develop a dangerous rhythm called torsades de pointes during this window.
How to Take
Take dofetilide twice daily, roughly twelve hours apart, at the same times each day. It can be taken with or without food. If a dose is missed, do not double up — skip the missed dose and take the next dose at the usual time. Avoid grapefruit juice, which can increase blood levels of dofetilide. The medication must not be stopped or restarted without the cardiologist’s involvement; restarting requires a return to hospital for monitoring, even at the same dose previously tolerated.
Sources
- Tikosyn (dofetilide) capsules — full prescribing information. Pfizer Inc. Available via DailyMed at dailymed.nlm.nih.gov Primary US prescribing information; source of the dosing matrix, contraindicated drug list, drug-interaction PK data (cimetidine, ketoconazole, TMP/SMX), and adverse-event incidence rates cited in this monograph.
- FDA Supplement Approval / Release of REMS Requirement for Tikosyn (dofetilide) Capsules. January–March 2016. accessdata.fda.gov Documents the FDA’s release of the formal REMS program while retaining the inpatient initiation requirement in the boxed warning.
- FDA Supplement Approval Letter for Tikosyn (dofetilide). 2019. accessdata.fda.gov Source for the current FDA-labeled QTc thresholds, dosing algorithm steps, and monitoring schedule.
- Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group. N Engl J Med. 1999;341(12):857–865. doi:10.1056/NEJM199909163411201 DIAMOND-CHF — established mortality neutrality and the 3.3% TdP rate (25/762 patients) in heart failure that informs current risk stratification.
- Køber L, Bloch Thomsen PE, Møller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet. 2000;356(9247):2052–2058. DIAMOND-MI — confirmed mortality neutrality post-MI and informed the renal-adjusted dosing protocol that lowered TdP rates compared with earlier non-adjusted regimens.
- Singh S, Zoble RG, Yellen L, 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. 2000;102(19):2385–2390. doi:10.1161/01.CIR.102.19.2385 Pivotal trial supporting FDA approval; defined the 500 mcg BID dose as the most effective regimen modified by the dosing algorithm.
- Pedersen HS, Elming H, Seibaek M, et al. Risk factors and predictors of torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving dofetilide. Am J Cardiol. 2007;100(5):876–880. doi:10.1016/j.amjcard.2007.04.020 DIAMOND substudy quantifying female sex and NYHA class III–IV as independent TdP predictors.
- Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation. Circulation. 2024;149(1):e1–e156. doi:10.1161/CIR.0000000000001193 Defines the role of dofetilide in atrial fibrillation rhythm control, including recommendations for use in heart failure and structural heart disease.
- Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation. 2018;138(13):e272–e391. doi:10.1161/CIR.0000000000000549 Provides framework for managing acquired QT prolongation and torsades de pointes during antiarrhythmic therapy.
- Mounsey JP, DiMarco JP. Cardiovascular drugs. Dofetilide. Circulation. 2000;102(21):2665–2670. doi:10.1161/01.CIR.102.21.2665 Authoritative review of dofetilide pharmacology, electrophysiology, and clinical role.
- Lenz TL, Hilleman DE. Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000;20(7):776–786. Practical clinical pharmacology review covering dosing, monitoring, and interactions.
- Jaiswal A, Goldbarg S. Dofetilide induced torsade de pointes: mechanism, risk factors and management strategies. Indian Heart J. 2014;66(6):640–648. doi:10.1016/j.ihj.2013.12.021 Comprehensive review of the mechanism, modifiable risk factors, and acute management of dofetilide-induced TdP; source for the timing distribution of TdP events within DIAMOND populations.
- Wolbrette DL, Hussain S, Maraj I, Naccarelli GV. A quarter of a century later: what is dofetilide’s clinical role today? J Cardiovasc Pharmacol Ther. 2019;24(1):3–10. Contemporary review of dofetilide’s place in current AF rhythm-control practice, off-label uses, and real-world conversion data.
- Tham TC, MacLennan BA, Burke MT, et al. Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans. J Cardiovasc Pharmacol. 1993;21(3):507–512. Original human pharmacokinetic characterization establishing the ~10-hour half-life and renal-dependent clearance.
- Allen MJ, Nichols DJ, Oliver SD. The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing. Br J Clin Pharmacol. 2000;50(3):247–253. Defines steady-state pharmacokinetics relevant to the twice-daily dosing schedule used clinically.
- Naksuk N, Sugrue AM, Padmanabhan D, et al. Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation. J Interv Card Electrophysiol. 2019;54(2):189–196. doi:10.1007/s10840-018-0476-2 Modern observational study quantifying the contemporary TdP rate (~0.8%) and identifying modifiable contributors in hospitalized AF patients.