Atrial Fibrillation and Flecainide - Safety, Effectiveness and Quality of Life Outcomes

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Abstract

Flecainide is a class IC antiarrhythmic agent indicated for patients with atrial fibrillation without any evidence of structural heart disease. This brief review of four recent studies on flecainide focuses on safety aspects, efficacy and the debate on impact on quality of life in this patient population. This article also briefly summarises data from the Cardiac Arrhythmia Suppression Trial (CAST) and the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, which investigated the effect of antiarrhythmics such as flecainide on morbidity and mortality. When administered according to recommended guidelines, flecainide is safe and is not associated with increased mortality. It is effective for the treatment of atrial fibrillation, improving quality of life in these patients.

Acknowledgement: Editing was provided by Touch Briefings. Adapted from the original publication by Droogmans and Provenier.1
Support: The publication of this article was funded by Meda Pharmaceuticals. The views and opinions expressed are those of the authors and not necessarily those of Meda Pharmaceuticals.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Frank Provenier, AZ Maria Middelares, Dienst Cardiologie, Kortrijksesteenweg 1026, 9000 Gent, Belgium. E: frankprovenier@azmmsj.be
Received date
28 June 2010
Accepted date
21 July 2010
Citation
European Cardiology - Volume 6 Issue 3, 2010;44-49
DOI
http://dx.doi.org/10.15420/ecr.2010.6.3.44

Atrial fibrillation (AF) is defined as a supraventricular tachycardia with rapid uncoordinated atrial activation, beat-to-beat irregularity and frequently rapid ventricular rate.2 It is the most frequently observed sustained arrhythmia in clinical practice.3 An estimated 12 million individuals in the EU and 2.3–10 million in the US have AF, and these numbers are expected to increase as the age of the population in developed countries increases.3,4 AF is associated with a high risk of stroke, heart failure and hospitalisation.5–7 It is not a benign condition,8 but is associated with increased morbidity and mortality.9 AF is particularly common among the elderly and often requires medical treatment.10 It is a chronic disorder, whether paroxysmal or persistent, and patients are likely to experience recurrence at some point.11 AF impairs quality of life (QoL) both physically and mentally. Patients with AF rate the QoL impact of AF as moderate to severe, and both patients and physicians rate AF as a life-threatening condition.12 AF causes palpitations at rest and upon exertion, shortness of breath and a reduction in physical ability during exertion.13 AF patients frequently experience anxiety about their disease and alter their lifestyles to avoid aggravating their symptoms. Such an impact on QoL particularly affects younger patients, who may be used to a more active lifestyle.14 Additionally, the impact of AF on QoL may extend to the relatives of patients with the condition.13
Despite the fact that AF is associated with impaired functional capacity and reduced QoL, as well as significant morbidity and mortality, the current approach to management fails to maintain stable sinus rhythm (SR) in the majority of patients. In a position paper, Cosio et al. assigned delayed rhythm control and the failure to identify associated cardiovascular conditions in many patients with newly detected AF as the most likely reasons for AF becoming intractable in a large proportion of patients. This is probably due to a lack of overall awareness regarding the importance of AF together with insufficient scientific understanding of the underlying remodelling processes. If AF is recognised as the result of a slow structural remodelling process, even the first documented episode of AF may be considered a late event. Even the first recorded episode may have been preceded by a number of asymptomatic or unrecognised episodes.15 Early repeated cardioversion alone appears to be insufficient to revert remodelling enough to stabilise SR.16 Early treatment of AF, including rhythm control together with aggressive detection and management of associated conditions, may help to prevent electrical and structural remodelling. Furthermore, it may allow arrest in progression or even reversal of the arrhythmogenic changes in the atria, although this strategy is thus far untested.15

Flecainide, an orally administered class IC antiarrhythmic drug (AAD), is used to manage cardiac arrhythmias.17,18 It is a potent inhibitor of the cardiac (Nav1.5) Na+ channel, causing prolongation of the cardiac action potential and the refractory period in cardiomyocytes, thereby slowing conduction of the electrical impulse within the heart.19 The greatest effect of flecainide is on the His–Purkinje system. It is indicated in patients without structural heart disease for the prevention of paroxysmal supraventricular tachycardias (PSVTs), including atrioventricular (AV) nodal re-entrant tachycardia, AV re-entrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms. It is also indicated in paroxysmal AF/flutter (PAF) associated with disabling symptoms.

The Cardiac Arrhythmia Suppression Trial

An initial study conducted in 38 patients with organic heart disease and a history of sudden cardiac arrest or recurrent sustained ventricular tachycardia treated with flecainide indicated that this particular class IC AAD was effective in the treatment of life-threatening refractory ventricular arrhythmias.20 However, the subsequent Cardiac Arrhythmia Suppression Trial (CAST), a randomised, prospective study, revealed that the use of class IC AADs such as flecainide after myocardial infarction (MI) was associated with excess mortality due to malignant arrhythmias.21 As indicated in the drug information leaflet, flecainide can be considered for the treatment and prevention of certain symptomatic and disabling ventricular arrhythmias in the absence of left ventricular dysfunction and coronary disease.22 Interestingly, a recent study published in Nature Medicine demonstrated that flecainide prevented catecholaminergic polymorphic ventricular tachycardia, first in mice and then also in two patients.23 However, since the CAST study, class IC AADs are no longer recommended for the treatment of ventricular arrhythmias.24 Current contraindications for treatment with flecainide are ischaemic heart disease, hypertrophic cardiomyopathy, hypertension with left ventricular hypertrophy, congested heart failure, high-degree AV block and complete bundle branch block.
The treatment of AF must be conducted with caution in view of the growing incidence of this arrhythmia in the ageing population and its impact on morbidity, particularly ischaemic stroke,25 and mortality.9 Maintenance of SR has the advantage of preserving physiological conduction with AV coupling, which relieves symptoms such as dyspnoea and palpitations and may slow progression to permanent AF due to electrical remodelling.26

However, the treatment of AF has been marked over recent years by the more frequent use of second-and third-generation class II beta-blockers, such as metoprolol and bisoprolol, instead of the class IC AADs, such as flecainide and propafenone. The tendency to overlook the use of flecainide and propafenone is mainly due to the pro-arrhythmic effect of these drugs, as emphasised by several studies.

The Atrial Fibrillation Follow-up Investigation of Rhythm Management Study

More recent randomised studies have also fallen short of being able to demonstrate any advantage of AADs in terms of mortality compared with a rate-control strategy in patients with AF. This was the case in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study and in the RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) study, published simultaneously in the New England Journal of Medicine in 2002.27,28 A post hoc analysis of the AFFIRM study also showed that non-cardiovascular mortality was increased in the rhythm-control arm.10
However, there are a number of reasons why these results led to erroneous conclusions concerning the AADs included. These were retrospective analyses of the results of the AFFIRM study, which in addition did not have sufficient statistical power. The high mortality was shown to be due to pulmonary disease and cancers, which are not known to be adverse effects of flecainide. Moreover, amiodarone was the most frequently prescribed AAD (~40%), while flecainide was only used in a minority of cases (4.5–13%). It is therefore not possible to attribute a potential excess of non-cardiac mortality to a single AAD. Although the study also included patients with a history of coronary artery disease (CAD) and/or left ventricular dysfunction, the incidence of de novo arrhythmias, certainly malignant disorders such as torsades de pointes, was low.29
The increased non-cardiac mortality in the case of antiarrhythmic treatment in the AFFIRM study was diametrically opposed to the recent findings reported by Andersen and colleagues.30 Their study retrospectively analysed the risk of death related to the use of AADs for the treatment of AF in a cohort of patients identified using the Danish National Patient Registry, a nationwide registry of all hospitalisations in Denmark set up in 1978. A total of 141,500 patients with first-time AF as a primary or secondary diagnosis between 1995 and 2004 were identified for the study, with a mean follow-up of 3.2 years. A total of 40,823 patients (29%) received AADs; of these patients, 2.4% of cases were treated with flecainide, 2.6% with propafenone, 16.5% with sotalol and 7.3% with amiodarone.

After correction for potentially confounding variables, such as age, gender, co-morbidities and the use of concomitant medications, an excess mortality was observed in the patient group not treated by AADs. The lowest mortality was observed in the flecainide group (relative risk [RR] 0.38, 95% confidence interval (CI) 0.32–0.44) compared with propafenone (RR 0.65, 95% CI 0.58–0.71), sotalol (RR 0.65, 95% CI 0.63–0.67) and amiodarone (RR 0.94, 95% CI 0.89–1.00) (see Figure 1). Increased mortality was observed after termination of treatment with AADs, particularly for flecainide and propafenone. The mortality rate was lower, compared with no AADs, during the first 30 days following initiation of AADs, corresponding to the period during which the pro-arrhythmic effect is expected. In this registry, patients treated with class IC AADs had a lower prevalence of co-morbidity and less use of concomitant treatments compared with patients treated with amiodarone, demonstrating that strict compliance with the indications for safe use of AADs is associated with low mortality.
These findings were confirmed in a meta-analysis of the safety of flecainide in patients with supraventricular arrhythmias.31 This meta analysis was based on 122 prospective studies including patients with preserved left ventricular function and no structural heart disease, in which 4,811 patients were treated with flecainide. Eight deaths (0.17%) were observed in the flecainide group, including three non-cardiac deaths (cancer, suicide and uraemia). Three of these patients had CAD and two patients may have died as a result of a cardiac problem, compared with one patient in the control group (not significant). Flecainide-induced arrhythmias were significantly less frequent than in the control group (treated with other AADs or placebo). Cardiac adverse effects from this analysis are summarised in Figure 2. However, an increase of non-cardiac adverse events (AEs) was observed in the group treated with flecainide (17%) compared with the control group (11%, p=0,06). These AEs consisted of vertigo, visual disorders and other central nervous system effects (see Figure 3). These effects were already known and did not affect compliance. This meta-analysis supports the safety of flecainide for the treatment of supraventricular arrhythmias in patients free of any structural heart disease.

A prospective study was conducted to assess the efficacy, safety and influencing factors of flecainide for cardioversion in high-risk patients.32 A total of 106 consecutive patients with recent-onset AF and known structural heart disease and/or elevated Prospective Cardiovascular Munster (PROCAM) score33 (>41, meaning a 10-year risk of acute coronary events ≥5.2% based on age, cholesterol and glucose level, blood pressure, smoking status and familial history) received 300mg oral flecainide for cardioversion. Patients who had MI in the preceding six months were excluded from the study. Life-threatening arrhythmias, including ventricular arrhythmias, AV conductance abnormalities and atrial flutter, did not occur in any of the study participants. The calculated mean PROCAM score reflecting the cardiovascular risk was 44.1±0.55. In patients with successful cardioversion the PROCAM score was 41.5±0.56, compared with 45.7±0.74 in patients without successful cardioversion (p<0.001). This observation was supported by the differentiated analyses of patient risk factors. The conversion rate with flecainide was lower in patients presenting with CAD, hypertension or dilated cardiomyopathy compared with patients having none of these diseases (RR 1.83, 95% CI 1.19–2.82; p=0.018) and was lower in patients under angiotensin-converting enzyme (ACE) inhibitor co-medication (RR 2.3, 95% CI 1.12–4.26; see Figure 4). A total of 43 patients (40.6%) experienced successful restoration of SR when treated with flecainide; of these, 36 (34%) developed asymptomatic sinus bradycardia. Limited arrest of a sinus beat following initiation of SR directly after successful electrical cardioversion was documented in 16 patients (15%). The authors concluded that, when monitored correctly, flecainide was safe and effective for cardioversion in patients with structural heart disease or those at elevated cardiovascular risk. They acknowledged that further randomised trials were needed to establish the use of flecainide for cardioversion in this patient population.
More recently, a prospective study was conducted to assess the therapeutic management of 376 patients presenting with a recurrent or new-onset AF at the emergency department (ED) of a tertiary care hospital during a two-year period, and to identify parameters associated with successful pharmacologic cardioversion.34 Patients with evidence of acute congestive heart failure, neurological symptoms or acute coronary syndrome were excluded from further analysis. In this study, cardioversion of AF was successful in 168 of the 376 patients within six hours. Flecainide was the most effective drug, with a primary response rate of 95% (see Figure 5).

Moreover, a significantly higher response rate was observed with flecainide compared with ibutilide (76%; p=0.014) and the combination of digoxin and diltiazem (69%; p=0.003). An increase in the successful conversion rate to 66% was observed when flecainide, ibutilide or amiodarone was administered. While the overall conversion rate was 45% at six hours, 86% of patients who received flecainide or ibutilide successfully responded to treatment. However, low primary response rates were observed with amiodarone (36%), digoxin (19%) and diltiazem (18%). The adverse effects experienced by patients on the different treatment regimens are summarised in Table 1. No cases of readmission due to AF were reported after successful cardioversion to SR within a 24-hour time-frame. Low adherence to the recommended guidelines was reported in this study, and only 33% of patients with acute AF were treated with drugs recommended by the American Heart Association (AHA)/American College of Cardiology (ACC)/European Society of Cardiology (ESC) guidelines, which contributed significantly to the observed results. The lack of adherence to treatment guidelines was an important contributor to the low response rates to digoxin, magnesium and diltiazem. Conversely, the high response rate to flecainide and the low rate of severe AEs reported with this drug were largely due to good adherence to treatment guidelines. Therefore, acute AF should be treated with the most effective drugs, such as flecainide and ibutilide, and, based on previously published data,35 flecainide is considered to be the most suitable drug for the treatment of AF in the ED.
Flecainide has been shown to be a highly effective agent for pharmacological cardioversion of recent-onset AF. Although its use in preventing the recurrence of AF after DC conversion has not been tested in randomised trials, it does increase arrhythmia-free survival36 in comparison with no treatment, with similar efficacy to amiodarone.37 Insufficient data exist to comment on the safety of flecainide for the prevention of the recurrence of persistent AF; however, when flecainide is used to treat patients with no evidence of CAD, it does appear to lower the risk of serious AEs. Notably, no comparative studies between the therapeutic value of the various AADs with that of AF ablation have been conducted to date. Further to ensuring enhanced efficacy as a result of the absence of arrhythmia, new AADs must also ensure a reduction in mortality.

Correct Treatment of Atrial Fibrillation Can Improve Patient Quality of Life

While there has been a plethora of studies regarding the safety of AADs, there have been few that have truly evaluated the outcomes for patients in terms of measures other than mortality and morbidity. AF is well known to affect the QoL of patients;13,14 therefore, examining QoL outcomes for patients now seems a logical future direction. More frequently published studies are examining QoL in patients being treated for AF.
An international, open-label study was recently conducted in hospitals, cardiology centres and private practices across France, Belgium and Italy with the aim of evaluating the impact of the control of symptomatic PAF on QoL.38 Patients were treated with controlled-release flecainide (flecainide CR) over a 48-week period and categorised as having either controlled or uncontrolled symptomatic PAF at inclusion. Of the 229 treated patients, 217 were analysed for QoL (123 with controlled and 94 with uncontrolled symptomatic PAF at inclusion). Generic and disease-specific self-administered QoL questionnaires were completed by the patients at baseline, week 12, week 24 and week 48. The clinical success rate was similar for both controlled (defined as no more than one symptomatic PAF episode per six months) and uncontrolled groups (defined as two or more symptomatic PAF episodes per six months): 89/126 (70.6%) versus 66/96 (68.8%). A total of 35 patients experienced AEs thought to be related to the study drug and 7.9% of patients were withdrawn from the study due to an AE. In this study, patients with uncontrolled symptomatic PAF at baseline had an inferior QoL to those with controlled symptomatic PAF. Following treatment with flecainide CR, their QoL improved to a level comparable to that of controlled patients. The maximum effect was at week 24 and the improvement was maintained up to week 48. Baseline QoL scores were maintained in the controlled group following treatment with flecainide CR. This study showed that the use of QoL questionnaires could be valuable for therapeutic decision-making and for follow-up evaluation of patients with symptomatic PAF. Furthermore, the safety findings reflected the known clinical safety profile of flecainide.
Examination of QoL in AF could be improved by a better understanding of the dimensions in which patients are most affected, as most QoL analyses are quite general. Recently, an observational, prospective, multicentre study was conducted across 29 Spanish centres to assess the QoL of AF patients by means of a self-administered QoL questionnaire that was proposed to discriminate between AF patients and patients with prior MI.39

The AF-QoL questionnaire consisted of 18 items with psychological, physical and sexual activity domains that were each standardised for a score between 0 (worst health-related [HR] QoL) and 100 (best HRQoL). A total of 417 AF patients were enrolled in the study and were divided into three groups: an intervention group (AF patients receiving a new therapeutic intervention according to physician evaluation; n=257), a clinically stable group (according to physician evaluation; n=84) and a control group (patients in a stable condition for more than one year after an MI; n=76). Follow-up visitation was at one month for the clinically stable group and at 3±1 months for the intervention group. The most prevalent symptoms in AF patients at inclusion were palpitations (77.6%), dyspnoea (65.1%), dizziness/syncope (37.0%) and chest discomfort (36.9%). A statistically significant improvement was observed in the number and severity of symptoms in both groups of AF patients by the end of the follow-up period (p<0.01). The questionnaire was fully completed by 89.4% of patients. In patients who received a new therapeutic intervention, the AF-QoL effect size was 1.05 (large effect size) in those who reported an improvement in their health status and 0.24 (small effect size) in those who reported no change in their health status (see Table 2). Patients with AF who had a higher percentage of clinical symptoms such as palpitations, chest discomfort and dyspnoea had lower scores (worse HRQoL) in the AF-QoL questionnaire. The overall AF-QoL scores, including the physical and psychological domains, were significantly higher in patients with a lower frequency of symptoms (p<0.05), indicating a better HR QoL.
Although AF has a major impact on morbidity, mortality and QoL, it is not always perceived as a serious health threat. In view of this, an international quantitative survey was conducted by the AF Awareness and Risk Education (AF AWARE) group (an international coalition of organisations with an interest in AF) to examine the level of understanding of, perception of and attitudes towards the cardiovascular risks associated with AF. The study was undertaken in 11 countries in 2009 to investigate patient (n=825) and cardiologist (n=810) perceptions of AF, preferences for communicating information on AF and burden of AF. Both patients and physicians considered AF life-threatening (55 and 43%, respectively), although physicians were more concerned about the risk of stroke and hospitalisations than were patients, whereas patients were more concerned about the risk of death. One in four patients felt unable to explain AF and more than one-third were worried about or fearful of their disease (see Table 3).

Approximately half of physicians (51%) wanted more patient information, with over 60% viewing the available information as poor or difficult to find. Patients relied on hospital specialists and their GPs for information. The majority of patients (83%) reported symptoms, although 75% were reportedly satisfied with their AF therapies. AF patients, often with associated diseases, made an average of nine visits to physicians per year. Physicians considered AF difficult and time-consuming to manage. Overall, patients and physicians considered the impact of AF on QoL as moderate to high.12
In summary, this review outlines some of the evidence for the safe and effective treatment of AF patients with flecainide, and suggests that satisfactory measures of safety and efficacy can be achieved when adherence to the recommended guidelines from the AHA/ACC/ESC is practised. Furthermore, the use of flecainide for the treatment of supraventricular arrhythmias is not associated with a documented increase of mortality in correctly selected patients. As indicated in international guidelines, the presence of structural and ischaemic heart disease must be excluded before initiation of treatment.40 Flecainide has an effect on maintaining SR in patients with PAF and is also partially effective in patients with persistent AF. In the long term there is a need to link the efficacy and safety of AADs to other patient outcomes measures, one of which is undoubtedly QoL. Improvements in QoL are important to patients, particularly younger patients, in whom there is a desire to not only control the symptoms but also to reduce the risk of subsequent progression to permanent AF and to limit the impact of their condition on their ability to work and carry out normal daily activities.

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