Introduction
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice with a prevalence reaching 5% in patients >65 years old and an incidence that increases progressively with age.1,2 The maintenance of sinus rhythm, while leading to an improvement of haemodynamic function and exercise tolerance, and consequent reduction of thromboembolic risk and symptoms relief, may favour a better quality of life (QoL). According to the most recent guidelines,3 class IC anti-arrhythmic drugs are considered first choice in patients without significant structural heart disease. Flecainide is effective in preventing AF recurrences in 31-61% of the cases, according to different studies.4-7
Unfortunately, class IC anti-arrhythmic drugs are also associated with a poor tolerability profile, which can lead to high discontinuation rates and potential serious side effects.8 Therefore, the majority of patients who experience a recurrence of AF or have tolerability issues usually stop the drug to seek therapeutic alternatives. The efficacy of β-blockers for maintenance of sinus rhythm is low,9 but adding a β-blocker to a class IC drug can represent an interesting approach in preventing arrhythmic events and for overall rhythm control effectiveness, especially in patients with an increased sympathetic tone. Beta-blockers may also reduce AF-related symptoms and are usually effective in rate control, especially in highly symptomatic patients with frequent high-rate paroxysms.10 Moreover, they may represent a good choice in the presence of arterial hypertension with initial signs of cardiac organ damage.11
The aim of the present study was to test efficacy and safety of a combination of flecainide and metoprolol in preventing AF clinical recurrences during a 1-year follow-up, defined as symptomatic AF episode or electrocardiogram (ECG) documentation of AF during planned or unplanned visit. The secondary endpoint was the assessment of QoL over 1-year follow-up.
Methods
Study population
This prospective, randomized, open-blinded, single-centre pilot study included all consecutive patients, admitted in the Cardiology and Arrhythmology Clinic of the University Hospital ‘Ospedali Riuniti’ in Ancona, Italy, from October 2011 to September 2013. Inclusion criteria were age ≥18 years and a recent (<7 days) conversion to sinus rhythm of paroxysmal or persistent symptomatic AF.
Exclusion criteria were previous anti-arrhythmic drug prescription, recent (within 6 months) acute coronary syndrome or stroke, heart failure New York Heart Association class III or IV, severe left ventricular dysfunction with left ventricular ejection fraction (LVEF) <0.40, atrioventricular conduction disorders (atrioventricular block, complete left bundle branch block, and bi-fascicular block), heart rate (HR) <40 b.p.m., sick sinus syndrome, systolic blood pressure <100 mmHg at admission, thyroid dysfunction, and severe pulmonary, renal, or liver disease. Patients with psychiatric or neurological disorders that could alter QoL evaluation were also excluded. The present study has been approved by our local Ethics Committee and complies with the Declaration of Helsinki. All patients gave their written informed consent.
Randomization and study intervention
After enrolment, patients were randomized into three groups: group A (flecainide and metoprolol), group B (flecainide only), and group C (metoprolol only). Flecainide was titrated in groups A and B, according to the same protocol. All patients started with an oral dose of 50 mg b.i.d.; if the drug was tolerated, the dose was then increased up to 75 mg b.i.d. after 3 months and up to 100 mg b.i.d. after 6 months. Patients in group A also received metoprolol 50 mg b.i.d., up-titrated to 75 mg b.i.d. after 3 months and up to 100 mg b.i.d. after 6 months if tolerated. Patients in group C received only metoprolol at a starting dose of 50 mg b.i.d., which was then up-titrated to 75 mg b.i.d. after 3 months and up to 100 mg b.i.d. after 6 months if tolerated. No patient in group B assumed any kind of medication for rate-control indication during the follow-up period.
Data collection
After enrolment, a detailed clinical history was collected and physical examination was performed. A standard 12-lead ECG was acquired at a paper speed of 25 mm/s and a scale of 10 mm/mV (Cardioline Delta 60 Plus, Vignate, Milano, Italy). A complete transthoracic echocardiogram was performed in all patients (Vivid 7 Pro, GE-Vingmed Ultrasound, Horten, Norway). Complete 2D, colour, and continuous-wave Doppler echocardiographic images were acquired. Left ventricular ejection fraction was assessed by modified biplane Simpson’s method. Quality of life assessment was performed at baseline and at 3, 6, 9, and 12-month follow-up periods. The generic SF-36 questionnaire and the Atrial Fibrillation Severity Scale (AFSS) were administered by two trained professionals at each visit. Clinical history, physical examination, and a 12-lead ECG were repeated during each follow-up visit at 3, 6, 9, and 12 months. A transthoracic echocardiogram was repeated at the end of the follow-up period.
Study endpoints
The primary endpoint was the incidence of clinical recurrence over 1-year follow-up, as defined by ECG documentation of a symptomatic AF episode during unscheduled visit or by ECG documentation of AF during planned visits at 3, 6, 9, and 12 months.
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The secondary endpoint was QoL variation over 1-year follow-up, as assessed by the SF-36 and AFSS questionnaires.
Statistical analysis
Sample size calculations were performed to have a >80% power to detect a difference of ≥20% in estimate recurrence-free survival during a 12-month follow-up period (with α = 0.05) between combination therapy group and each of the two control groups, using a Kaplan-Meier analysis with a log-rank P test. We assumed a 12-month recurrence-free survival of 40% in the flecainide-only group12 and of 50% in the metoprolol group.9 A separate sample size calculation was performed for each control group (group A vs. group B and group A vs. group C), and the biggest sample size derived (72 patients) was used to set enrolment target in each group. Quantitative variables were checked for normality by the Kolmogorov-Smirnov test. Normally distributed variables were described as mean ± standard deviation. Not-normally distributed variables were described as median and first-to-third interquartile range. Analysis of variance (ANOVA) adjusted by age and sex was used to compare normally distributed quantitative variables. Kruskal-Wallis ANOVA was used to compare non-normally distributed quantitative variables. Categorical variables were assessed by using χ2 analysis and described as absolute or relative prevalence. Kaplan-Meier analyses with a log-rank P test were used to compare recurrence-free survival among the three groups. Bonferroni adjustment was used for multiple comparisons. Pre-specified, ad interim, Kaplan-Meier analyses were computed after 3 and 6 months in order to rule out potential early differences in recurrence-free survival. General linear model for repeated measurements was used in order to test for difference in mean HRs during the 12-month follow-up. SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Values of P < 0.05 (two-tailed) were taken as statistically significant.
Results
General characteristics of the population
One-hundred seventy-three patients were enrolled: 80 patients in group A, 72 patients in group B, and 21 patients in group C. General characteristics of the population are shown in Table 1. No significant differences were seen in baseline parameters between the three groups.
Primary endpoint
During the first ad interim analysis, group C showed a significantly higher incidence of AF recurrence (76.2%). Therefore, enrolment in this group was prematurely stopped for ethical reasons. All patients exited the study and were treated according to the current clinical practice.
Type of atrial fibrillation
Quality of life
Patients randomized to combination therapy experienced a significant improvement of QoL when compared with patients assigned to flecainide-only regimen. SF-36 questionnaires demonstrated higher values in group A patients in physical scores, such as bodily pain, general health, and physical health, when compared with group B patients (Table 4), irrespective of AF type. In contrast, no differences were seen regarding mental SF-36 items. AFSS questionnaire also showed a statistically significant improvement in group A patients regarding global well-being (P = 0.031), although no differences were found regarding other items such as AF burden, health-care utilization, and symptoms score.
Safety
Overall, drug-related side effects were quite rare. In group A, two patients discontinued treatment due to reported fatigue, and another one discontinued treatment due to concomitant renal problems. In group B, one patient discontinued flecainide due to fatigue, whereas another patient reported a severe case of dermatitis, requiring medication stop and specific treatment.
Development of other tachyarrhythmias was also quite rare. In group A, one patient developed a 2:1 conduction atrial flutter, and one patient developed atrial tachycardia with 4:1 ventricular conduction. In group B, two patients developed a 2:1 conduction atrial flutter, and one patient developed a 4:1 conduction atrial flutter. All the adverse events were tolerated by the patients and did not lead to clinical instability or long-term sequelae. No episodes of 1:1 conduction atrial flutter were reported during the follow-up.
Discussion
The potential role of the adrenergic system in the genesis of arrhythmic events during class IC anti-arrhythmic therapy first emerged in a post hoc analysis of the CAST trial,13 which demonstrated that relative mortality risk in patients treated with beta-blockers and IC was reduced when compared with the placebo group. Different laboratory studies14,15 have also demonstrated that inward Na+ current could be modulated by beta-adrenergic receptors in a variety of cell lines. These previous observations may suggest a potential additional effect of adrenergic blockade and Na channel blockers (with a potential beneficial effect of beta-blocking in preventing proarrhythmic events). Similar results were reached by Myerburg et al.,16 demonstrating the effectiveness of propranolol in suppressing the proarrhythmic effects of flecainide, suggesting a possible clinical interaction between these drugs and the autonomic function. These data suggest that the beta-adrenergic modulation interferes with conduction slowing and increases the refractory period induced by flecainide (reducing the potential proarrhythmic effects), leading to the evidence that beta-blockers could be administered in association with IC anti-arrhythmic drugs during rhythm control strategy.
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Our data are consistent with recent findings showing that different combinations between two anti-arrhythmic drugs could be the answer to the still unmet clinical need of a safe and effective rhythm control therapy. In fact, although the combination of a class III drug, such as dronedarone, and ranolazine (class I effect) has already been shown to be effective in preventing AF recurrences,17 more recently mathematical models of cardiomyocytes have been used to demonstrate that K+-channel blockade could potentially improve the anti-AF effects of Na+-channel blockers.18 All these findings, along with ours, could potentially open the road for more research on anti-arrhythmic drug combinations.
Our study did show a lower rate of symptomatic AF recurrences during metoprolol plus flecainide therapy compared with flecainide alone at 1-year follow-up. These results were, however, confirmed in the persistent AF subgroup but not in the paroxysmal one. The study is underpowered to detect significant difference in this subgroup of patients, but the present finding can help in generating some hypotheses on the different mechanisms triggering paroxysmal and persistent AF. In particular, lack of efficacy of metoprolol in patients with paroxysmal AF could be explained by the fact that firing from pulmonary veins is likely the main cause in triggering AF paroxysms. In fact, delayed afterdepolarizations due to sarcoplasmic reticulum Ca2+ leak have been shown to promote cellular arrhythmogenesis in patients with paroxysmal AF.19 In contrast, the increased effectiveness of metoprolol in persistent AF could be explained by the positive impact on left ventricular hypertrophy regression and to the negative chronotropic effect at rest and during exercise, both of which have been demonstrated to improve diastolic filling and thus to reduce atrial stretch.20
The addition of metoprolol contributed to reduce the daily maintenance dose of flecainide in the combination group, with a possible benefit in reducing dose-related adverse events and thus an increased tolerability. The combination therapy also enhanced QoL when compared with monotherapy, probably due to the reduced arrhythmic recurrences and lower drug doses.21 Global well-being and physical health seem to improve according to the questionnaires provided, and patients reported no significant differences in mental items during follow-up. It must be said, however, that effect of combination therapy on QoL may have been due, at least in part, to the beneficial effect of β-blockers in reducing symptoms associated with high HR, and this option was not available by protocol in patients randomized to flecainide-only. Such results, if confirmed in larger trials, may confirm the role of combination therapy as a first-line therapy in reducing symptomatic AF with better safety and physical tolerability, overcoming the existing limits of the present anti-arrhythmic therapy status.
Limitations
This study was not planned to detect brief, asymptomatic periods of AF. This is a major limitation as we cannot exclude that the difference seen could be, at least in part, partly due to unrecognized asymptomatic AF paroxysms in the combination therapy group. Also, although the study was powered to test the primary endpoint in the whole population, overall numbers were quite small. Thus, the effect of chance cannot be completely ruled out, and further investigation is needed to confirm our data, especially in the subgroup of patients with persistent AF.
Although this study is underpowered to detect potential differences in the incidence of other tachyarrhythmias, atrial flutter and atrial tachycardia were quite rare, and none of the atrial flutter reported led to a 1:1 conduction. This finding could add some evidence on the safety of this combination therapy in everyday ambulatory practice.
Conclusion
Metoprolol and flecainide combination therapy improves effectiveness of rhythm control, reducing recurrences in persistent symptomatic AF up to 30% over 1-year follow-up period. Combination therapy leads to a better tolerability, with reduction of side effects and overall improved compliance. Combination therapy with flecainide and metoprolol positively affects physical aspects of quality of life when compared with a flecainide-only regimen.
Supplementary material
Supplementary material is available at Europace online.
Funding
This work was supported by the Marche Polytechnic University (2013-363).
Conflict of interest: none declared.
References
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