SEARCH

SEARCH BY CITATION

Keywords:

  • atrial fibrillation;
  • flecainide;
  • proarrhythmia;
  • safety;
  • sudden cardiac death

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

Abstract.  Almroth H, Andersson T, Fengsrud E, Friberg L, Linde P, Rosenqvist M, Englund A (Örebro University Hospital, Örebro; Danderyd Hospital and Karolinska Institutet at Danderyd Hospital, Stockholm; and Karolinska Institutet at Stockholm South Hospital, Sweden). The safety of flecainide treatment of atrial fibrillation: long-term incidence of sudden cardiac death and proarrhythmic events. J Intern Med 2011; 270: 281–290.

Objective.  To assess the safety of long-term treatment with flecainide in patients with atrial fibrillation (AF), particularly with regard to sudden cardiac death (SCD) and proarrhythmic events.

Design.  Retrospective, observational cohort study.

Setting.  Single-centre study at Örebro University Hospital, Sweden.

Subjects.  A total of 112 patients with paroxysmal (51%) or persistent (49%) AF (mean age 60 ± 11 years) were included after identifying all patients with AF who initiated oral flecainide treatment (mean dose 203 ± 43 mg per day) between 1998 and 2006. Standard exclusion/inclusion criteria for flecainide were used, and flecainide treatment was usually combined with an atrioventricular-blocking agent (89%).

Main outcome measure.  Death was classified as sudden or nonsudden according to standard definitions. Proarrhythmia was defined as cardiac syncope or life-threatening arrhythmia.

Results.  Eight deaths were reported during a mean follow-up of 3.4 ± 2.4 years. Compared to the general population, the standardized mortality ratios were 1.57 (95% confidence interval (CI) 0.68–3.09) for all-cause mortality and 4.16 (95% CI 1.53–9.06) for death from cardiovascular disease. Three deaths were classified as SCDs. Proarrhythmic events occurred in six patients (two each with wide QRS tachycardia, 1 : 1 conducted atrial flutter and syncope during exercise).

Conclusion.  We found an increased incidence of SCD or proarrhythmic events in this real-world study of flecainide used for the treatment of AF. The findings suggest that further investigation into the safety of flecainide for the treatment of patients with AF is warranted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

Atrial fibrillation (AF) accounts for more than one-third of all hospitalizations for arrhythmia. The condition is associated with increased morbidity and mortality, usually related to stroke or heart failure [1]. Some AF patients have very mild or no symptoms, whereas others are severely symptomatic. Anti-arrhythmic treatment is often indicated in the latter group. After electrical cardioversion, at least 50% of patients will relapse to AF during the first year, despite prophylactic anti-arrhythmic drug therapy [2, 3]. In addition to their limited efficacy, anti-arrhythmic drugs are sometimes poorly tolerated and some of the side effects are serious. The risk of proarrhythmia is a particularly severe problem. The CAST trial [4, 5] reported a 2.5-fold increased risk of sudden cardiac death (SCD) in patients treated with flecainide/encainide compared with placebo in a population with structural heart disease. Subsequently, flecainide has been contraindicated in this population. Flecainide is widely used and recommended by the American and European heart societies as a first-line treatment for patients with symptomatic AF [6, 7] and no evidence of structural heart disease. However, information regarding the long-term safety of flecainide in AF patients is limited. Most previous studies have had a relatively short follow-up and been conducted in patients with different forms of supraventricular re-entry tachycardia, not in patients with AF. Moreover, very little information is available regarding the outcome of flecainide treatment in clinical practice outside the strict protocols and monitoring of a clinical trial. The main objective of this study was to assess the safety of long-term treatment with flecainide in AF patients, particularly with regard to SCD and proarrhythmia.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

Subjects

All patients with AF who initiated oral flecainide treatment between 1998 and 2006 at our institution were identified using the International Classification of Diseases 10th revision (ICD-10) classification for AF (I48) and flecainide as search criteria in our computerized medical records system. The cohort was followed prospectively, collecting demographic data and electrocardiogram (ECG), transthoracic echocardiogram and exercise test results in a database. Death was classified according to medical records, results from autopsies and information from the Swedish Death Register. SCD was defined as death that occurred ‘suddenly and unexpectedly’ in a patient with an otherwise stable condition and included witnessed deaths (with or without documentation of arrhythmia) and deaths that were not witnessed if the patient had been seen within 24 h before death but did not have premonitory heart failure, myocardial infarction or another clear cause of death [8]. Proarrhythmia was defined as cardiac syncope or a life-threatening arrhythmia. Follow-up was completed in December 2008.

Flecainide treatment

Standard criteria were applied for flecainide treatment [6, 7]. All AF patients for whom anti-arrhythmic therapy was indicated underwent a transthoracic echocardiogram before starting flecainide therapy. If ischaemia could not be evaluated by an exercise test, for example in patients with a disability or a pacemaker, myocardial scintigraphy or coronary angiography was performed. All patients were admitted to hospital for 3 days whilst flecainide treatment was initiated. At discharge, patients were instructed to make contact if they experienced arrhythmia or the symptoms of ischaemic heart disease (IHD), dizziness or syncope. In case of breakthrough AF, a dose adjustment up to usually not more than 300 mg per day flecainide was evaluated. Plasma flecainide concentrations were not measured. Follow-up was performed in the outpatient clinic at least once a year. At these visits, a 12-lead ECG was recorded, but no other investigations were made unless new symptoms (e.g. angina, dyspnoea) presented. Treatment was discontinued if considered to be ineffective, at the occurrence of intolerable side effects, at suspicion of structural heart disease, or in the case of abnormal findings on the ECG, such as new bundle branch block (BBB) or QRS duration >50% compared to pretreatment. All patients were prescribed a beta-blocker or non-dihydropyridine calcium antagonist together with flecainide if there were no contraindications. Anticoagulation therapy was administered according to international guidelines.

Statistical analysis

We used descriptive statistics and graphical methods to characterize the cohort. Normally distributed data were expressed as mean ± standard deviation. To determine the observed mortality, we compared the observed number of deaths with the expected number of deaths using mortality rates from the general Swedish population (2000–2008) by calculating standardized mortality ratios (SMRs). The SMRs were adjusted for age (5-year groups) and gender and calculated for all-cause mortality (ACM) and cardiovascular disease (CVD). CVD was defined as IHD (ICD-10 I20-25), cardiac arrhythmia (ICD-10 I46-49), heart failure (ICD-10 I50) and stroke (ICD-10 I61, 63-64). SMRs were presented with confidence intervals, assuming that the observed and expected number of deaths followed a Poisson distribution. Events, defined as SCD and proarrhythmia [i.e. 1 : 1 atrial flutter (AFL), wide QRS tachycardia or syncope during exercise], were presented as annualized incidence rates per 100 person-years with associated confidence intervals assuming a poisson distribution. To characterize patients with events, they were grouped together and compared against the rest of the cohort. Proportions were compared by Pearson’s chi-square test without continuity correction or Fisher’s exact test when appropriate and Student’s t-test for continuous normally distributed variables. The Wilcoxon rank sum test was used to compare variables with skewed distributions. A P-value <0.05 was considered significant. Statistical calculations were made with JMP® 7 (SAS Institute Inc., Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

Patient characteristics

Patient demographics are presented in Table 1. A total of 112 patients were started on flecainide treatment between 1998 and 2006 with follow-up until 1 December 2008. Of these patients, 104 (93%) had AF alone and eight (7%) had AF and AFL. All patients had assessed the use of conventional beta-blocking therapy prior to flecainide treatment.

Table 1. Demographic and clinical characteristics at the initiation of flecainide treatment
VariableNo. of patients (n = 112)
  1. Data are presented as means ± standard deviation (ranges) for continuous variables or n (%) for dichotomous variables. AF, atrial fibrillation; IHD, ischaemic heart disease; CHF, cardiac heart failure; TIA, transient ischaemic attack; EF, ejection fraction; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, acetylsalicylic acid; AAD, anti-arrhythmic drug.

  2. CHADS2 score, one point assigned for each of the risk factors: congestive heart failure, hypertension, age >75 years and diabetes; two points for stroke or TIA.

Male72 (64)
Age (years), mean ± SD60 ± 11
Atrial fibrillation
 Paroxysmal57 (51)
 Persistent55 (49)
Concomitant disease
 Stable IHD4 (4)
 CHF
 Valvular disease4 (4)
 Hypertension39 (35)
 Previous stroke/TIA13 (12)
 Diabetes mellitus2 (2)
 Pacemaker3 (3)
CHADS2 score (mean ± SD)0.64 ± 0.87
 0 p62 (55)
 1 p35 (31)
 2 p8 (7)
 3 p7 (6)
Medical therapy
 Beta-blocker91 (81)
 Calcium antagonist26 (23)
 Digoxin1 (1)
 ACE inhibitor/ARB28 (25)
 Statin19 (17)
 Warfarin62 (55)
 ASA33 (30)
 Number of AADs used prior to flecainide0.78 ± 0.68
Creatinine (μmol L−1), mean ± SD
 Male89 ± 14
 Female75 ± 13
Exercise test (max workload, Watts), mean ± SD171 ± 62
EF (%),mean ± SD61 ± 6
Scintigraphy2 (2)
Angiography7 (6)

Cardiac evaluation prior to initiation of therapy

Transthoracic echocardiogram revealed clinically significant but stable valvular disease in four patients (moderate mitral, tricuspid and aortic insufficiency in one, two and one patients, respectively). Left atrial enlargement (>45 mm) was found in 26 patients (23%). All patients had an ejection fraction (EF) >45%, and the mean EF was 61 ± 6%. A symptom-limited exercise test was performed in 97 (87%) patients. No patient had signs of myocardial ischaemia, according to the ECG, or suffered from chest pain during the test. The mean maximal workload was 171 ± 62 W. Coronary angiography was performed in seven patients <6 months prior to flecainide initiation (six patients with AF and chest pain and one with aberrant AF misinterpreted as ventricular arrhythmia). Two other patients underwent myocardial scintigraphy without signs of ischaemia. Four patients had a history of IHD, two patients had a percutaneous transluminal coronary angioplasty because of angina pectoris and two had a prior subendocardial infarction with a normal coronary angiography. In total, eight patients were prescribed flecainide despite our intention not to treat patients with structural heart disease (four patients each with significant valvular disease and IHD).

Pharmacological treatment

The mean daily dose of flecainide was 203 ± 43 mg. Treatment was initiated inhospital with continuous telemetry monitoring for 3 days in all patients. During this period, no proarrhythmic events were recorded in any patient. The mean QRS duration increased by 14%, from 95 ms before treatment to 108 ms during the steady state. The QRS duration did not increase >50% in any patient. Flecainide was combined with a beta-blocker (n = 91) and/or non-dihydropyridine calcium antagonist (n = 26) in 100 patients (89%). Twelve patients were not treated with a beta-blocker or non-dihydropyridine calcium antagonist because of contraindications or intolerable side effects. Warfarin was given to 62 (55%) patients and aspirin to 33 (30%) patients. Twenty-four patients (21%) did not receive either warfarin or aspirin, and 11 of them were undertreated according to CHADS2 criteria.

Follow-up

The mean duration of flecainide treatment was 3.4 ± 2.4 years. Flecainide treatment was discontinued in 67 (60%) patients. The reasons for discontinuation included a lack of efficacy in 36 patients (32%), noncardiac side effects in seven patients (6%) and successful radiofrequency ablation in six (5%). Eighteen patients (16%) discontinued treatment because of cardiac side effects. Six of these patients were classified as having proarrhythmia; three patients had proarrhythmia documented by 12-lead ECG or telemetry (two with monomorphic wide QRS tachycardia, one with 1 : 1 AFL with broad QRS complex and syncope) (Fig. 1). Two patients experienced syncope during physical exercise associated with palpitations, and one patient had episodes of 1 : 1 AFL during rhythm monitoring associated with symptoms (no ECG available). Five patients developed symptomatic structural heart disease during treatment (IHD in two patients and congestive heart failure in three), and treatment was stopped in these patients as well as in another seven because of symptomatic sinus bradycardia (n = 2) or the development of new BBB (n = 5). In total, 11 (10%) patients received a pacemaker during follow-up. The main reason for this high figure was that six patients were included in a study in which a pacemaker algorithm for the prevention of AF was evaluated, and the remaining five patients developed symptomatic episodes of sinus arrest (n = 4) or syncope because of total atrioventricular (AV) block (n = 1).

image

Figure 1. ECG or telemetric documentation for patients with proarrhythmia (25 mm s−1).

Download figure to PowerPoint

Mortality and comparisons with the general population

Eight patients died during flecainide treatment. Five deaths were nonsudden because of cancer (n = 1), stroke (n = 2), ST elevation myocardial infarction (n = 1) and amyotrophic lateral sclerosis (n = 1). Three deaths were classified as SCD. This figure corresponded to a mean annual mortality rate of 2.1% compared with the expected value of 1.3% from age- and sex-adjusted population statistics. The SMRs were 1.6 (95% CI 0.68–3.09) for ACM and 4.2 (95% CI 1.53–9.06) for death from CVD during flecainide exposure (Table 2a).

Table 2. Summary of results in 112 patients treated with flecainide
(a) SMRs for all-cause mortality and cardiovascular deaths
 Observed (n)Expected (n)SMR95% CI
  1. SMR, standardized mortality rate; CVD, cardiovascular death; CI, confidence interval; SCD, sudden cardiac death; Observed (n), observed number of patients; Expected (n), expected number of patients.

All cause mortality85.101.570.68–3.09
CVD61.444.161.53–9.06
(b) Annualized incidence rates/100 person-years
 Observed (n)Annualized incidence rate95% CI
SCD and proarrhythmia92.381.73–7.18
SCD30.790.78–11.06
Proarrhythmia61.591.39–8.24
All-cause mortality82.111.63–7.46

Patients with SCD or proarrhythmia

The characteristics of patients with SCD or proarrhythmia are presented in Table 3, and data from some patients with proarrhythmic events are shown in Fig. 1. The first SCD was in a 69-year-old man with paroxysmal AF and a dual-chamber pacemaker because of sick sinus syndrome. After 9 days on flecainide, the patient was admitted to the emergency unit with ventricular fibrillation, and cardiopulmonary resuscitation was performed without success. Autopsy revealed arteriosclerosis in the coronary vessels and an acute subendocardial, posterior–lateral infarction and pulmonary oedema. The second patient was a 66-year-old man with persistent AF. This patient was found dead in his home in March 2006 after 20 months of treatment with flecainide. At the request of his relatives, no autopsy was conducted.

Table 3. Characteristics of patients with SCD (no. 1–3) and proarrhythmia (no. 4–9)
NoSex/AgeDiseaseSmokerHereditary IHDDys- lipidemiaCHADS2 scoreGFR mL min−1EF (%)LVHDays on fDose (mg per day)Beta – blockerQRSpre (ms)QRSpost (ms)QRSdiff (%)Autopsy (Yes/No)Proarrhythmia
  1. *Weight not available. Creatinine normal.

  2. Abbreviations: M, male; FM, female; IHD, ischaemic heart disease; GFR, glomerular filtration rate (Cockcroft Gault formula); EF, ejection fraction; LVH, left ventricular hypertrophy; f, flecainide; HT, hypertension; AFL, atrial flutter; DM, diabetes mellitus; TI, tricuspid insufficiency.

  3. CHADS2 score, one point assigned for each of the risk factors: congestive heart failure, hypertension, age >75 years and diabetes; two points for stroke or TIA.

1M/69 NoNoNo0*50No9200YesYes
2M/66HTNoNoNo19365No616300Yes889811No
3FM/55DM, StrokeNoNoYes313250No1903300Yes88969Yes
4M/75StrokeNoNoNo36155No64200Yes10014040Wide QRS tachycardia
5M/68HT, DMNoNoYes213165No534200Yes11212814Syncope
6FM/52Stroke, HTNoNoNo313560No1043300Yes1021064Wide QRS tachycardia
7M/65TINoNoNo09450No1849200No8496141 : 1 AFL + syncope
8M/59HTNoNoNo111968No1616200Yes86106231 : 1 AFL
9FM/58 NoNoYes010960No205200Yes8210022Syncope

The third patient was a 55-year-old woman with type II diabetes and persistent AF. This patient unexpectedly became unconscious whilst horseback riding with her daughter. When the ambulance arrived 10 min later, ECG showed ventricular fibrillation. Autopsy revealed a suspicious septal acute myocardial infarction. The coronary vessels showed signs of slight to moderate arteriosclerosis but no significant visible stenosis or thrombotic material.

When comparing clinical characteristics, patients in the event group received higher doses of flecainide (233 ± 50 vs. 200 ± 41 mg per day, = 0.025) and more patients had diabetes mellitus (n = 2 vs. n = 0, = 0.0058) compared with patients without events. Patients with events also tended to have a higher creatinine level at baseline (91 ± 18 vs. 83 ± 15 μmol L−1, = 0.13) and slightly lower EF (58 ± 7% vs. 61 ± 6%, = 0.12). In the total cohort, the incidence of SCD or proarrhythmia was 8% during a mean follow-up of 40 months, resulting in an annual incidence of almost 2.5%. The corresponding annualized incidence rate per 100 person-years was 2.4 (Table 2b).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

The main finding of this observational study was that flecainide treatment is associated with a fourfold increased risk of cardiovascular mortality compared with the general Swedish population. We also observed a 2.5% annual incidence of SCD or proarrhythmia during follow-up. These harmful effects were not prevented by careful evaluation during drug initiation and follow-up or by treatment with AV-blocking agents.

Mortality and AF in general

In general, AF is associated with an increased relative risk of mortality, ranging from 1.2 to 2 after adjusting for age and comorbidity. The findings in our cohort regarding ACM were consistent with previous findings [9–11]; however, we found a fourfold increased risk of CVD, which is a higher relative risk than previously described in patients with paroxysmal or persistent AF [12].

The findings of the CAST study unexpectedly revealed a 2.5-fold increased risk of arrhythmic death and/or cardiac arrest in patients treated with flecainide or encainide compared with placebo during a median drug exposure of 10 months. Patients with severely impaired left ventricular function seemed to be at increased risk (9.5% with flecainide/encainide versus 3.6% with placebo), but even higher relative risks were found in patients with moderately impaired left ventricular function (EF >30%) and prior myocardial infarction [4, 5]. Because the CAST results were reported, the major indication for flecainide is in patients with symptomatic AF and no structural heart disease. It is important to note that no randomized controlled trial with sufficient power to evaluate the effect on mortality has been conducted in AF patients, and only limited information is available on the safety of flecainide in this population. This discussion is even more relevant after the publication of large randomized trials that have failed to show mortality benefits of rhythm- compared with rate-control strategies in AF patients [13–15].

Mortality and proarrhythmia

Because of the few cases of proarrhythmic events reported in somewhat different populations, comparison with previous studies is difficult and must be made cautiously. In our observational cohort, there were eight deaths during flecainide treatment, three of which were classified as SCD. Earlier studies revealed a total number of eight deaths in the AF population receiving flecainide (three because of noncardiac causes, four because of structural heart disease, and information was not available in the remaining case) [16–21]. In cases in which information was available, the occurrence of death ranged from 1 day to 2 months after flecainide treatment initiation. By comparison, none of our three observed cases of SCD had signs of structural heart disease prior to beginning flecainide treatment or during follow-up until death occurred at 9 days, 20 and 63 months after the start of treatment. To date, one randomized controlled trial has compared flecainide with placebo and five have compared flecainide with an alternative anti-arrhythmic treatment in AF populations. No deaths were reported in the 313 patients in these six studies with a median flecainide exposure time of 12 months. Loss to follow-up was reported in all trials except one, and none was blinded [22–27].

Because most previous data were from patients with supraventricular arrhythmia, safety has primarily been addressed in this population. In a meta-analysis by Wehling (n = 4811, exposure time 2015 patient-years, mean flecainide dose 216 ± 65 mg per day, mean age 55 ± 13 years, 60% men), the yearly ACM rate was estimated to be 0.397 per 100 person-years [28]. The corresponding ACM rate in our cohort was 2.1 per year per 100 patient-years (n = 112, exposure time 378 patient-years, mean flecainide dose 203 ± 43 mg per day, mean age 60 ± 11 years, 64% men). A large Danish register study recently presented results in which treatment with flecainide was not associated with an increased risk of death in AF patients, compared with those not receiving anti-arrhythmic therapy [29]. The mortality rate in the flecainide cohort in the Danish study (n = 3356; 2.54 per year per 100 person-years) was slightly higher to that in our study. The somewhat lower mortality rate in our cohort might be explained by slight differences in comorbidity. The main difference is that we had information regarding the causes of death (including three cases of SCD).

The postulated explanation for SCD is flecainide’s proarrhythmic potential when observational findings characterize patients at risk [30–32]. The definition of proarrhythmia varies considerably, but it most often refers to a rapid ventricular response during AF or AFL [19, 33, 34]. Contrary to previous observations, the patients in our cohort who experienced proarrhythmic events, compared with those who did not, did not tend to have a longer QRS duration and were not older, and the events occurred in a linear fashion over time, whereas earlier findings indicated higher risk during the early treatment period [20]. In addition, concomitant cardiovascular risks (CHADS2 score) were stable in all patients with events during follow-up, when a change might have explained an increased risk of SCD or proarrhythmia. AV-blocking agents have also been proposed to protect against rapid ventricular rates, which might occur because of the atrial refractory properties of flecainide. By comparison, one patient in our cohort with proarrhythmic events was not adequately blocked (patient no. 3, Table 2), and none of the other patients with SCD or proarrhythmia reached more than 80% of their estimated maximum pulse when evaluated by a symptom-limited exercise test.

Limitations

A major limitation in the present study is the observational design in which all information was collected retrospectively from medical records, and that the collected data during follow-up did not follow a predefined study protocol. Ideally, we would have preferred to include a control group receiving another anti-arrhythmic drug or beta-blocker and to randomly allocate patients to treatment groups; however, this study design was not applicable in the circumstances. Instead, we used age- and sex-adjusted population statistics from the general population as a control group for ACM and cardiovascular death. When compared to population statistics, some diagnostic inaccuracies and misclassifications may have occured regarding causes of death, which might have introduced surveillance bias because the patients in our cohort may have been more thoroughly examined. The fact that the patients were drawn from a geographically defined community (Örebro, Sweden) and patient selection was limited to those seen at the Department of Cardiology, Örebro University Hospital, also raises questions about generalizability. This selection process may have resulted in a population with poorer general health, but in cases in which anti-arrhythmic therapy has been discussed, especially flecainide, these patients have traditionally been referred for evaluation, initiation and follow-up. In our cohort, autopsy was performed in two of three patients whose deaths were classified as SCD with findings that might indicate death caused by tachyarrhythmia. As there are other conditions that might evolve rapidly and lead to SCD, there is also a risk of inaccuracy regarding this definition [35]. Finally, there may have been a lack of compliance because we cannot be sure that patients took their prescribed flecainide.

Clinical implications

According to the recent American College of Cardiology/American Heart Association and the European Society of Cardiology guidelines [6, 7], flecainide has a role for first-line treatment in patients with AF alone or AF and hypertension without any evidence of structural heart disease. A transthoracic echocardiogram is recommended as a minimal clinical evaluation to identify patients at risk, whereas exercise testing is mandatory in older patients with risk factors. In addition, all of our patients were monitored during the first 3 days of treatment, which revealed no proarrhythmia and did not help to identify patients at risk. In this study, SCD and proarrhythmia occurred despite the use of concomitant AV-blocking agents in AF patients without structural heart disease, renal insufficiency or excessive QRS prolongation during flecainide treatment. This finding questions the impact of available clinical tools used to identify patients at risk; indeed only one event occurred amongst the eight patients who received flecainide treatment despite the presence of structural heart disease at the initiation of treatment (patient no. 7, Table 2). This is further supported by a higher SMR for CVD (increased from 4.16 to 4.39), instead of an anticipated decrease, when the eight patients who received flecainide despite having structural heart disease were excluded. It is interesting that there were no cases of SCD or proarrhythmia in the 67 patients who discontinued flecainide treatment in our cohort (no loss to follow-up during a mean period of 37 months).

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

In this real-world study of flecainide in AF patients, we found a substantially increased incidence of SCD or proarrhythmic events. Our findings indicate that SCD or proarrhythmia might occur, even in a relatively healthy AF population, despite careful evaluation before flecainide initiation and during follow-up. Further investigation into the safety of flecainide treatment is warranted in AF patients.

Conflict of interest statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References

Mårten Rosenqvist has lectured for Sanofi-Aventis, Nycomed and Boehringer-Ingelheim and acted as a national coordinator in clinical trials sponsored by Astra Zeneca, Sanofi-Aventis and Bristol-Myers Squibb. He is also a member of the Boehringer-Ingelheim Swedish advisory committee regarding haemostasis. He has received unrestricted research grants from Boehringer-Ingelheim and Sanofi-Aventis.

Leif Friberg is a consultant to Sanofi-Aventis, Boehringer-Ingelheim and Bristol-Myers Squibb.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflict of interest statement
  9. References
  • 1
    Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 68791.
  • 2
    Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1993; 71: 55863.
  • 3
    Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 1990; 82: 19329.
  • 4
    The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 40612.
  • 5
    Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 7818.
  • 6
    Fuster V, Ryden LE, Cannom DS et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace 2006; 8: 651745.
  • 7
    Camm AJ, Kirchhof P, Lip GY et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12: 1360420.
  • 8
    Myerburg RJ, Kessler KM, Bassett AL, Castellanos A. A biological approach to sudden cardiac death: structure, function and cause. Am J Cardiol 1989; 63: 15126.
  • 9
    Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 94652.
  • 10
    Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998; 32: 695703.
  • 11
    Wyse DG, Love JC, Yao Q et al. Atrial fibrillation: a risk factor for increased mortality – an AVID registry analysis. J Interv Card Electrophysiol 2001; 5: 26773.
  • 12
    Friberg L, Hammar N, Pettersson H, Rosenqvist M. Increased mortality in paroxysmal atrial fibrillation: report from the Stockholm Cohort-Study of Atrial Fibrillation (SCAF). Eur Heart J 2007; 28: 234653.
  • 13
    Wyse DG, Waldo AL, DiMarco JP et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 182533.
  • 14
    Van Gelder IC, Hagens VE, Bosker HA et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347: 183440.
  • 15
    Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008; 358: 266777.
  • 16
    Anderson JL, Gilbert EM, Alpert BL et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80: 155770.
  • 17
    Crijns HJ, Van Gelder IC, Van Gilst WH, Hillege H, Gosselink AM, Lie KI. Serial antiarrhythmic drug treatment to maintain sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter. Am J Cardiol 1991; 68: 33541.
  • 18
    Gulizia M, Mangiameli S, Orazi S et al. A randomized comparison of amiodarone and class IC antiarrhythmic drugs to treat atrial fibrillation in patients paced for sinus node disease: the Prevention Investigation and Treatment: a Group for Observation and Research on Atrial arrhythmias (PITAGORA) trial. Am Heart J 2008; 155: 1007.
  • 19
    Pietersen AH, Hellemann H. Usefulness of flecainide for prevention of paroxysmal atrial fibrillation and flutter. Danish-Norwegian Flecainide Multicenter Study Group. Am J Cardiol 1991; 67: 7137.
  • 20
    Sihm I, Hansen FA, Rasmussen J, Pedersen AK, Thygesen K. Flecainide acetate in atrial flutter and fibrillation. The arrhythmogenic effects. Eur Heart J 1990; 11: 1458.
  • 21
    van Wijk LM, den Heijer P, Crijns HJ, van Gilst WH, Lie KI. Flecainide versus quinidine in the prevention of paroxysms of atrial fibrillation. J Cardiovasc Pharmacol 1989; 13: 326.
  • 22
    Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77: 66A71A.
  • 23
    Carunchio A, Fera MS, Mazza A et al. A comparison between flecainide and sotalol in the prevention of recurrences of paroxysmal atrial fibrillation. G Ital Cardiol 1995; 25: 5168.
  • 24
    Chimienti M, Cullen MT Jr, Casadei G. Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias. Report from the Flecainide and Propafenone Italian Study (FAPIS) Group. Eur Heart J 1995; 16: 194351.
  • 25
    Naccarelli GV, Dorian P, Hohnloser SH, Coumel P. Prospective comparison of flecainide versus quinidine for the treatment of paroxysmal atrial fibrillation/flutter. The Flecainide Multicenter Atrial Fibrillation Study Group. Am J Cardiol 1996; 77: 53A9A.
  • 26
    Steinbeck G, Doliwa R, Bach P. Therapy of paroxysmal atrial fibrillation. Cardiac glycosides alone or combined with anti-arrhythmia agents? Dtsch Med Wochenschr 1988; 113: 186771.
  • 27
    Van Gelder IC, Crijns HJ, Van Gilst WH, Van Wijk LM, Hamer HP, Lie KI. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64: 131721.
  • 28
    Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002; 52: 50714.
  • 29
    Andersen SS, Hansen ML, Gislason GH et al. Antiarrhythmic therapy and risk of death in patients with atrial fibrillation: a nationwide study. Europace 2009; 11: 88691.
  • 30
    Morganroth J. Risk factors for the development of proarrhythmic events. Am J Cardiol 1987; 59: 32E7E.
  • 31
    Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 1986; 8: 60715.
  • 32
    Falk RH. Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med 1989; 111: 10711.
  • 33
    Alboni P, Botto GL, Baldi N et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med 2004; 351: 238491.
  • 34
    Pritchett EL, DaTorre SD, Platt ML, McCarville SE, Hougham AJ. Flecainide acetate treatment of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation: dose-response studies. The Flecainide Supraventricular Tachycardia Study Group. J Am Coll Cardiol 1991; 17: 297303.
  • 35
    Huikuri HV, Makikallio TH, Raatikainen MJ, Perkiomaki J, Castellanos A, Myerburg RJ. Prediction of sudden cardiac death: appraisal of the studies and methods assessing the risk of sudden arrhythmic death. Circulation 2003; 108: 1105.