• 
• 

Three Part Question

In [patients with atrial fibrillation and who are not significantly cardiovascularly compromised] is [flecainide better than placebo] at [reverting the patient back to sinus rhythm]?

Clinical Scenario

A 50 years old man attends the Emergency department with a 12 hours history of palpitations. He denies any history of previous ischaemic heart disease. He complains of no other symptoms other than mild dizziness. On clinical examination he has a normal BP, no signs of heart failure and an ECG shows him to be in AF with a rate of 140/min. You wonder if flecainide is better than placebo at cardioversion.

Search Strategy

Medline 1966- 09/ 2005 using the Ovid interface.
[(exp Atrial fibrillation OR atrial fibrillation.mp OR AF.mp) AND (exp flecainide OR flecainide.mp)].
Embase 1974-06/2005 using Dialog DataStar interface.
[(atrial ADJ fibrillation) AND (flecainide) AND (placebo)]
The Cochrane library was also searched (accessed 02/2005).
References of the articles retrieved were searched to identify further references.

Search Outcome

The Medline search produced 327 paper, Embase 90 studies, and Cochrane 63.
Reference review discovered no additional papers.
A total of 9 papers were found to be of sufficient quality and relevant to the 3 part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Anderson 1989	55 cardiology out-patients with paroxysmal AF (2 separate, documented episodes over a 4/52 period) given flecainide or placebo for 8/52 before crossing over to the other arm of the study. The dose of flecainide given was between 100 & 200mg twice daily, the actual dose being determined during a 3/52 dosing range phase before the trial started.	Double-blind, randomised cross-over trial.	1. Proportion of patients who remain free of episodes.	1. More patients remained AF free in the flecainide group (31% vs 8% for placebo [p=0.013]).	1. Small study. 2. Not ED setting. 3. 5 patients (9%) withdrawn from the study due to protocol violations but no intention-to-treat analysis was performed.
			2. Time to first attack.	2. Median time to first attack was 5x longer with flecainide (14.5 days vs 3 days with placebo [p<0.001]). Mean time was extended 3-fold (18 vs 7 days [p<0.02]).
			3. Average time between attacks.	3. Increased median time between episodes (6 days vs 27 days with placebo [p<0.001])
			4. Ventricular rate during attacks.	4. Statistically (p=0.017) but not clinically (5 bpm) reduction in heart rate with flecainide.
Villani 1990	37 patients admitted with AF (< 24 hours duration) given oral flecainide (19) (200mg with a 100mg dose after 2.5 hours if still in AF) or placebo (18).	RCT (single blinded).	Cardioversion over 24 hours.	Cardioversion rates: 95% for flecainide (74% needed only one dose of flecainide). 28% for placebo.	1. cardiology in-patients. 2. very small study. 3. no data on adverse events.
Pritchett 1991	28 cardiology out-patients with paroxysmal AF (at least 2 episodes during a 28/7 screening period) given ascending doses of flecainide (25, 50, 100, 150mg bd) for one month each, with a month of placebo randomly placed amongst the active treatments.	Double blind RCT	1. Proportion of patients free of AF during each treatment period.	1. Significant increase in proportion of event free patients with 150mg flecainide (61% vs 7% with placebo [p<0.01]).	1. Small study. 2. No assessment made of duration of episodes.
			2. Time to first episode.	2. In those who had episodes, there was a significant increase in median time to first episode (3 days with placebo, 14 days with flecainide 150mg [p<0.0125]).
			3. Time interval between attacks.	3. Increased median time between episodes (7 days with placebo vs >25 days with flecainide 150mg [p<0.0125]).
			4. Ventricular rate during episodes.	4. Statistically but not clinically significant reduction in heart rate during episodes (132 +/- 21 placebo; 119 +/- 18 with flecainide).
Donovan 1991	49 medical/ critical care in-patients with AF <72 hours duration and HR >120/min. (but no severe heart failure) randomised to 2mg/kg flecainide iv (max. 150mg) (n=25) or placebo (n=24). All patients were also given digoxin (0.5mg iv). This was a subset of a larger study that included post cardiac surgery patients.	Double blind RCT	Proportion of patients in sinus rhythm @ 1 & 6 hours.	Significantly more patients were in sinus rhythm with flecainide at both 1 hour (57% vs 14% with placebo [p=0.000013]) and 6 hours (67% vs 35% with placebo [p=0.003])	1. Small study. 2. Short period of observation.
Capucci 1992	43 patients admitted with AF (<7/7 duration), rate >70/min., randomised to 300mg oral flecainide (22) or oral placebo (21). This was a subset of a larger study comparing flecainide, amiodarone and placebo.	RCT (single blinded).	Rate of conversion to sinus rhythm at 3 and 8 hours.	Cardioversion rates were better with flecainide: 3 hours:68% for flecainide. 8 hours: 91% flecainide 48% placebo.	1. cardiology in-patients. 2. small study. 3. short follow-up time.
Capucci 1994	120 patients admitted with AF (<7/7 duration), rate >70/min., randomised to 300mg oral flecainide (58) or oral placebo (62). This was a subset of a larger study comparing flecainide, propafenone and placebo.	RCT (single blinded).	1. Rate of conversion to sinus rhythm at 3 and 8 hours.	1. 3 hours: 59% for flecainide. 8 hours: 78% flecainide 39% placebo.	1. cardiology in- patients. 2. small study. 3. short follow-up time.
			2. Adverse effects	2. None serious. Some proarrhythmic effects (fast atrial flutter) occurred even with placebo (21% placebo, 9% flecainide, but the numbers were too small to determine significance).
Botto 1994	126 patients with AF (<72 hours) given oral flecainide 300mg (n=34) or placebo (n=92). This was a subset of a larger study comparing flecainide, propafenone, digoxin, and placebo.	RCT	1 Cardioversion rate at 4 hours.	1. Flecainide was significantly better than placebo (59% vs 20% with placebo [p<0.001]).	1. Small study 2. Short follow up. 3. No demographic data given therefore cannot ascertain if groups were comparable. 4. Unable to ascertain the prevalence of structural heart disease or significant heart failure in the patients.
			2. Proarrhythmia rate.	2. There was no significant difference in arrhythmia rate (8.8% flecainide vs 4.3% placebo [NS]). All were regular atrial tachyarrhythmias.
Boriani 1998	190 cardiology in-patients with stable AF (<8/7 duration) randomised to either flecainide (300mg po) (n=69) or placebo (n=121) This was a subset of a larger study comparing flecainide, propafenone, amiodarone, and placebo.	RCT	Cardioversion rates at 1,3 and 8 hours.	1 hour 13% F; 9% P (NS). 3 hours 57% F; 18% P (p<0.01). 8 hours 75% F; 37% P (p<0.01).	Short follow up.
Romano 2001	188 patients with AF (HR >100/min) of <72 hours duration , given flecainide (2mg/kg over 20 mins) (n=138) or placebo (n=50)	RCT	1. Cardioversion rate at 24 hours.	1. Cardioversion rate significantly better with flecainide: 1 hour 72.5% F; 22.2% P (p<0.0001). 3 hours 80.4% F; 27.8% P (p<0.0001). 6 hours 86.2% F; 35.2% P (p<0.0005). 24 hours 89.8% F; 46.3% P (p<0.0001).	Small study.
			2. Side-effects	2. 10% bradycardia/ hypotension with flecainide vs 4% with placebo (NS). No malignant arrhythmias were noted in any patient.

Comment(s)

Paroxysmal AF. Two studies1,3 both indicated that oral flecainide (100-200mg orally twice daily) is effective at reducing the frequency of paroxysms although it does not seem to reduce rate acutely and there is no evidence to indicate whether it has any effect on reducing the duration of episodes. Acute AF. 5 studies2,5-8 indicated that oral flecainide (300mg) is effective at cardioverting stable AF of up to 1 week duration although none of the studies followed up patients beyond 24 hours. Cardioversion rates were significantly better beyond 3 hours although one study8 found that flecainide was no better than placebo at 1 hour. Cardioversion rates were: 1 hour not significant 3 hours 57-59% 4 hours 59% 8 hours 78-91% 24 hours 95% 2 further papers4,9 also found that iv flecainide (2mg/kg) was more effective than placebo at cardioverting stable AF of less than 72 hours duration. Both studies found that flecainide was significantly better than placebo from as early as 1 hour after treatment was given. Cardioversion rates were: 1 hour 57-72.5% 3 hours 80.4% 6 hours 67-86% 24 hours 89.8% Adverse Effects. 3 studies6,7,9 looked at adverse effects and none found evidence of increased risk of significant side-effects with flecainide. Unfortunately, the studies were too small for this finding to be certain, and so the advice to avoid flecainide in those with structural heart disease and cardiac failure should be followed in patients with AF.

Clinical Bottom Line

Flecainide, by both intravenous and oral routes, is better than placebo at cardioverting stable atrial fibrillation of any duration up to 1 week. More research is needed to elucidate adverse effects and long term outcomes. It is also effective at reducing frequency of episodes of paroxysmal AF and may be considered when discharging patients from the department.

References

1. 1. Anderson JL, Gilbert EM, Alpert BL, Henthorn RW, Waldo AL, Bhandari AK, Hawkinson RW, and Pritchett ELC. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo Circulation. 1989; 80; 1557-1570.
2. Villani GQ, Rosi A, Piepoli M, Gandolfini A, Groppi F, Groppi M, Arruzzoli S, Dieci G, and Gazzola U. The efficacy of oral treatment with flecainide for paroxysmal atrial fibrillation: correlation with plasma concentration. G Ital Cardiol. 1990; 20; 564-568.
3. Pritchett ELC, DaTorre SD, Platt ML, McCarville SE, and Hougham AJ. Flecainide acetate treatment of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation: dose-response studies J Am Coll Cardiol. 1991; 17; 297-303.
4. Donovan KD, Dobb GJ, Coombs LJ, Lee K-Y, Weekes JN, Murdock CJ, and Clarke GM. Reversion of recent-onset atrial fibrillation to sinus rhythm by intravenous flecainide. Am J Cardiol. 1991; 67; 137-1
5. Capucci A, Lenzi T, Boriani G, Trisolino G, Binetti N, Cavazza M, Fontana G, and Magnani B. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol. 1992; 70; 69-72.
6. Capucci A, Boriani G, Botto GL, Lenzi T, Rubino I, Falcone C, Trisolino G, Casa SD, Binetti N, Cavazza M, Sanguinetti M, and Magnani B. Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide. Am J Cardiol. 1994; 74; 503-505.
7. Botto GL, Bonini W, Broffoni T, CApelleti G, Falcone C, Lombardi R, Paulesu A, Pedraglio E, and Ferrari G. Regular ventricular rhythms before conversion of recent onset atrial fibrillation to sinus rhythm. PACE. 1994; 17; 2114-2117.
8. Boriani G, Biffi M, Capucci A, Botto G, Broffoni T, Ongari M, Trisolino G, Rubino I, Sanguinetti M, Branzi A, and Magnani B. Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols. PACE. 1998; 21; 2470-2474.
9. Romano S, Fattore L, Toscano G, Corsini F, Coppo A, Catanzaro M, Romano A, Martoni A, Caccavale F, Iodice E, Di Maggio, and Corsini G. Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation. Ital Heart J (Suppl). 2001; 2; 41-45.