Acute Management of Paroxysmal Atrial Fibrillation with Intravenous Flecainide plus Oral Beta-Blockers

: Background: Intravenous (IV) flecainide is recommended for the pharmacological car-dioversion of recent-onset atrial fibrillation (AF). The aim of this study was to study the efficacy and safety of IV flecainide, co-administered with oral b-blockers, for the cardioversion of paroxysmal AF. Methods: Single-center registry, initiated in the “Skylitseion” General Hospital of Chios in January 2020. The main inclusion criterion was IV flecainide administration plus oral b-blocker for recent-onset AF ( ≤ 48 h). The primary outcome was conversion to sinus rhythm at 2 h. Results: A total of 121 (73 males and 48 females, with mean age 61.4 years) consecutive, unselected patients who complied with the study protocol were included. A successful conversion to sinus rhythm at 2 h was achieved in 99 patients (success rate: 81.8%). The median conversion time was 11.7 min (varied from 3 to 23 min). Duration of hospitalization was significantly shorter in patients who were successfully cardioverted with IV flecainide (10.9 vs. 30.7 h, p < 0.001). No serious adverse events were recorded. Conclusion: This is one of the largest registries worldwide, evaluating the effectiveness and safety of IV flecainide co-administered with a b-blocker in the acute management of recent-onset AF. The successful conversion rate at 2 h is very high and quick with no serious adverse events.

Flecainide is among the first-line treatments both for cardioversion and sinus rhythm maintenance in AF patients without structural heart disease or coronary artery disease [1,2].Intravenous flecainide acetate was first introduced in Greek hospitals near the beginning of 2020, just before the COVID-19 pandemic in Greece, and is recommended with a class IA indication for the pharmacological cardioversion of recent-onset AF [3].Robust data from its use remain scarce [4].The aim of this study was to evaluate the efficacy and safety of intravenous flecainide plus oral b-blockers in the cardioversion of paroxysmal AF.

Patient Population
Our study was a single-center registry, initiated at the "Skylitseion" General Hospital of Chios in January 2020.Patients were included in the registry if presenting with recent-onset AF (≤48 h) lasting ≥30 min documented by a 12-lead ECG and having received intravenous (IV) flecainide (FLECARDIA®inj.sol.inf, 10 mg/mL, WinMedica/ Elpen, Athens, Greece) at the treating physician's discretion.Exclusion criteria were the presence of hemodynamic instability, severe structural or ischemic heart disease including left ventricular hypertrophy, significant valvular heart disease, previous cardiac surgery, any cardiomyopathy, coronary artery disease, atrial flutter, sick sinus syndrome, highdegree atrioventricular block, bifascicular block, abnormal electrolyte levels (especially hypo-or hyperkalemia), known sensitivity to flecainide, or regular use of oral flecainide or amiodarone.Continuous monitoring was applied during and after the administration of IV flecainide.All patients underwent a bedside cardiac echo to exclude structural or ischemic heart disease.Moreover, laboratory tests including cardiac enzymes, electrolytes and kidney function were performed for all patients in the emergency department to exclude ischemic heart disease or electrolyte imbalance.All patients were admitted to the Cardiology ward, where flecainide infusion took place under close monitoring.
This study was accomplished in accordance with the principles of the Declaration of Helsinki.The Scientific Committee of the Skylitseio General Hospital of Chios, Greece provided ethical approval for all study procedures.Patients were included in the registry after informed written consent was obtained.The study was registered in ClinicalTrials.govwith the ID NCT04991896.

Outcomes
The primary outcome was conversion to sinus rhythm at 2 h.Secondary outcomes were serious adverse events-proarrhythmic events (ventricular tachycardia, ventricular fibrillation, torsades de pointes, atrial flutter with 1:1 atrioventricular conduction, any arrhythmic event managed with defibrillation), severe hypotension (systolic blood pressure < 90 mmHg for >10 min or requiring inotropic support), discontinuation of the IV flecainide infusion for any reason and hospitalization duration.If no conversion to sinus rhythm was achieved at 2 h after flecainide infusion initiation, the patient was recorded as an "unsuccessful pharmacological cardioversion" and forwarded for direct current cardioversion (DCC).All patients were anticoagulated according to the current European Society of Cardiology Guidelines (ESC) for the management of AF [4].

Flecainide Administration
Flecainide was given as an IV infusion of 1.5 mg/kg (max 150 mg) in DW 5% over 10 min under continuous monitoring and took place in the Cardiology ward after receiving the results of the patients' blood tests in the emergency department.Additionally, the concomitant administration of a b-blocker under monitoring, to avoid the transformation of AF to atrial flutter with 1:1 conduction, was applied to patients who did not receive a b-blocker before their arrival and took place at the emergency department before the blood tests (at least 30 min prior to flecainide administration).B-blocker dose and type were at the discretion of the treating physician.The time interval from the end of the flecainide infusion up to when the restoration of sinus rhythm was achieved was recorded as the primary outcome.

Statistical Analysis
Statistical analysis was performed with the software IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, NY, USA).Normality tests were performed by the Shapiro-Wilk test.Normally distributed variables are presented as mean ± SD and not normally distributed variables are expressed as median (minimum-maximum).Comparisons between groups were performed with the t-test for independent samples and the Mann-Whitney U test for independent samples for normally and not normally distributed variables, respectively, while the chi-square test was used for comparisons between categorical variables.A p value of <0.05 was considered statistically significant.

Results
A total of 121 (73 males and 48 females, mean age 61.4 ± 8.2 years) unselected patients who complied with the study protocol were included in the registry.Table 1 shows the baseline characteristics of the whole cohort and the differences between the two groups.As observed, patients were middle-aged, with no history or signs of ischemic or structural heart disease, and their main comorbidities were arterial hypertension and dyslipidemia.The duration of the atrial fibrillation was 12 ± 6.7 h and the initial heart rate was 139 ± 17 bpm.All patients received an oral dose of the b-blocker at least 30 min before flecainide infusion initiation, most frequently bisoprolol and metoprolol.
When comparing the baseline characteristics between the pharmacologically converted (IV flecainide plus b-blocker) and the non-converted groups, no statistical differences were found.Binomial logistic regression also did not reveal any predictive factor of successful cardioversion.
IV flecainide successfully cardioverted 99 out of the 121 patients at 2 h, thus having a success rate of 81.8%.The conversion time varied from 3 to 23 min, with a median of 11.7 min.Patients that did not show a restored sinus rhythm received successful direct current cardioversion (DCC).No serious adverse events were recorded (Figure 1, Table 2).
The duration of the atrial fibrillation was 12 ± 6.7 h and the initial heart rate was 139 ± 17 bpm.All patients received an oral dose of the b-blocker at least 30 min before flecainide infusion initiation, most frequently bisoprolol and metoprolol.
When comparing the baseline characteristics between the pharmacologically converted (IV flecainide plus b-blocker) and the non-converted groups, no statistical differences were found.Binomial logistic regression also did not reveal any predictive factor of successful cardioversion.
IV flecainide successfully cardioverted 99 out of the 121 patients at 2 h, thus having a success rate of 81.8%.The conversion time varied from 3 to 23 min, with a median of 11.7 min.Patients that did not show a restored sinus rhythm received successful direct current cardioversion (DCC).No serious adverse events were recorded (Figure 1, Table 2).Moreover, patients who were successfully cardioverted with IV flecainide had a hospitalization duration of 10.9 h, significantly shorter than that (30.7 h) of the patients who remained in AF at 2 h (Table 2).

Discussion
Flecainide is indicated in the 2020 ESC AF guidelines (recommendation IA) for the pharmacological cardioversion of recent-onset AF after excluding ischemic or significant heart disease.This can be achieved either by oral or IV administration [3].Oral flecainide is available globally and can also be self-administered by selected outpatients as a 'pill-in-thepocket' treatment.IV flecainide is frequently used in emergency departments for acute AF cardioversion but is not marketed in all countries.IV flecainide has been available in Greek hospitals since the beginning of 2020 and provided the background to initiate our registry.
In recent-onset AF cardioversion, flecainide is very effective (conversion rate 50-96% at 1 h, reaching a plateau at 3-8 h), and has a short conversion time (mean time 30 min, ranging from 14 to 53 min), while a duration of AF ≤ 24 h results in a higher success rate (Figure 2) [1][2][3][4][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].In our registry, the successful conversion rate at 2 h was 81.8% with a median conversion time of 11.7 min.This is one of the shortest conversion times that have been reported and could be probably attributed to the concomitant use of b-blockers in all patients, which was not the case in other studies, or to the very short AF duration (mean of 12 h).The use of a b-blocker increases the safety of IV flecainide, reducing the rates of proarrhythmic events, and according to clinical experience may also increase the efficacy of flecainide in cardioversion.To our knowledge, our registry is the only study evaluating the effectiveness and safety of IV flecainide in co-administration with a b-blocker in 100% of AF patients.It is also one of the largest studies evaluating IV flecainide administration in the acute management of recent-onset AF in the emergency department (Figure 2).
Moreover, patients who were successfully cardioverted with IV flecainide had a hospitalization duration of 10.9 h, significantly shorter than that (30.7 h) of the patients who remained in AF at 2 h (Table 2).

Discussion
Flecainide is indicated in the 2020 ESC AF guidelines (recommendation IA) for the pharmacological cardioversion of recent-onset AF after excluding ischemic or significant heart disease.This can be achieved either by oral or IV administration [3].Oral flecainide is available globally and can also be self-administered by selected outpatients as a 'pill-inthe-pocket treatment.IV flecainide is frequently used in emergency departments for acute AF cardioversion but is not marketed in all countries.IV flecainide has been available in Greek hospitals since the beginning of 2020 and provided the background to initiate our registry.
In recent-onset AF cardioversion, flecainide is very effective (conversion rate 50-96% at 1 h, reaching a plateau at 3-8 h), and has a short conversion time (mean time 30 min, ranging from 14 to 53 min), while a duration of AF ≤ 24 h results in a higher success rate (Figure 2) [1,2,3,4,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].In our registry, the successful conversion rate at 2 h was 81.8% with a median conversion time of 11.7 min.This is one of the shortest conversion times that have been reported and could be probably attributed to the concomitant use of bblockers in all patients, which was not the case in other studies, or to the very short AF duration (mean of 12 h).The use of a b-blocker increases the safety of IV flecainide, reducing the rates of proarrhythmic events, and according to clinical experience may also increase the efficacy of flecainide in cardioversion.To our knowledge, our registry is the only study evaluating the effectiveness and safety of IV flecainide in co-administration with a b-blocker in 100% of AF patients.It is also one of the largest studies evaluating IV flecainide administration in the acute management of recent-onset AF in the emergency department (Figure 2).Compared with other antiarrhythmic drugs, IV flecainide achieves higher and faster conversion rates than amiodarone, propafenone, procainamide, ibutilide and dofetilide [2,4,28].Regarding the other medications, according to the ESC AF Guidelines, the indications of propafenone use for the cardioversion of paroxysmal AF are the same as flecainide, while vernakalant may be used IV with a conversion rate of 65-70% in 10 min for patients with paroxysmal AF without hypotension, recent ACS within 1 month, severe aortic stenosis or heart failure.So, compared to vernakalant, IV flecainide is more effective with longer conversion times, but with its wider availability and cost-effectiveness being of the utmost importance.Amiodarone remains the drug of choice for the safe restoration of sinus rhythm in patients with ischemic or structural heart disease if delayed cardioversion is consistent with the clinical situation.Moreover, compared to oral flecainide (conversion rate of 50-60% within 3 h) [13], IV flecainide is faster and more effective in cardioversion.Fast and safe cardioversion, which was achieved with the use of IV flecainide plus a beta-blocker in our study, looks really appealing, especially in this COVID-19 era where short hospital stays offer economic and safety benefits for patients and the national health system [29][30][31].In our cohort, hospitalization duration was almost three times shorter for patients who achieved initial conversion to SR with IV flecainide (Table 2).This could be attributed to the elimination of the waiting time for the DCC set-up preparations and subsequent follow-up.Furthermore, the treating physician probably feels more confident discharging a patient after an uncomplicated cardioversion in 20 min with just an IV drug infusion and a few hours of follow-up than when performing a DCC with some level of sedation and the possible need for anesthesiologic assistance.This short conversion time could result also in fewer hospital admissions by monitoring patients in short-stay units in the emergency department and discharging them immediately afterwards.
Serious adverse events with IV flecainide in the acute phase of AF, like proarrhythmic events or severe hypotension, are rare in most studies, and this was also the case in our registry.Three studies reported severe proarrhythmic events with an incidence of 2% for torsades de pointes (one patient) and 2% for atrial flutter with 1:1 conduction (one patient in each of the other two studies); however, the caveat here is that all these studies included patients with structural or coronary artery disease [21,25,27].Donovan et al. 1992 andDonovan et al. 1995, who reported severe hypotension rates of 21.6% and 23.5%, respectively, used a prolonged 30 min infusion regimen (instead of 10 min) and included patients with a history of previous cardiac surgery and coronary artery disease that could be associated with this [21,23].In general, it is of note that most studies with IV flecainide included patients with a history of structural heart disease or coronary artery disease that were excluded from our registry [17,[19][20][21][22][23][24][25][26][27].

Study Limitations
The limitations of our study are mainly associated with the study type (it is an openlabel, single-center registry), as well as any concomitant treatment allocations based on the treating physician's discretion.However, we tried to overcome these facts by establishing a pre-specified protocol with exclusion criteria for IV flecainide administration.Furthermore, 10% of patients with AF had already received sotalol as a b-blocker, which was their baseline antiarrhythmic treatment of AF, prior to IV flecainide administration (QTc was less than 460 ms).This group of patients received two antiarrhythmic drugs, and even though this combination is not recommended by the ESC AF Guidelines, there are articles reporting the combined used of flecainide and sotalol in patients with arrhythmogenic right ventricular cardiomyopathy and recurrent supra ventricular tachycardias [32][33][34][35][36].Moreover, in the study of Martínez-Marcos et al., registry sotalol was given to some patients in combination with flecainide [25].

Conclusions
Our registry is one of the largest studies worldwide, evaluating the effectiveness and safety of IV flecainide in co-administration with a b-blocker in the acute management of recent-onset AF (≤48 h).The success rate was high at 81.8% at 2 h, and quick with conversions to sinus rhythm achieved in ≤23 min, while no serious adverse events were recorded.This makes IV flecainide superior to oral flecainide in terms of efficacy and speed for the cardioversion of paroxysmal AF.In patients with paroxysmal AF and certain characteristics, the combination of IV flecainide with an oral beta-blocker resulted in the

Figure 1 .Table 2 .*
Figure 1.Success rate of IV flecainide cardioversion to sinus rhythm with time.The inlet shows in magnification the success rate in the first 25 min after infusion.IV: intravenous, SR: sinus rhythm.Table 2. Conversion time and adverse events of the IV flecainide cohort.Successful Conversion to SR at 2 h (n = 99)

Figure 1 .
Figure 1.Success rate of IV flecainide cardioversion to sinus rhythm with time.The inlet shows in magnification the success rate in the first 25 min after infusion.IV: intravenous, SR: sinus rhythm.

Table 1 .
Baseline characteristics and comparisons between groups.

Table 2 .
Conversion time and adverse events of the IV flecainide cohort.