A total of 33 genotype-positive CPVT patients from 21 families were started on flecainide at eight tertiary care centers (). All patients had persistent physical or emotional stress-induced ventricular arrhythmias documented by exercise testing, Holter recordings, or the ICD interrogation, and/or persistent symptoms of palpitations, syncope, cardiac arrest, or appropriate ICD shocks, while on β-blockers +/− Ca2+ channel blockers. Twenty-three (70%) of the patients were female. The median age at the start of flecainide therapy was 25 (range 7 to 68) years. Thirty-one (94%) patients were treated with β-blockers, and four (12%) of them also received Ca2+ channel blockers (). In one patient (#13), flecainide was stopped because of side effects before exercise testing could be repeated, in another patient (#27) the β-blocker dose was increased during flecainide treatment, and two patients (#7 and #30) did not receive β-blocker therapy when flecainide was started (). In the remaining 29 patients, exercise tests on combination therapy of flecainide with conventional drugs at unchanged or lower doses were available for analysis. In 17 (59%) patients, baseline exercise testing was performed less than 48 hours before flecainide initiation.
Baseline characteristics and flecainide therapy parameters
Flecainide therapy reduces exercise-induced ventricular arrhythmias
Flecainide treatment improved the ventricular arrhythmia score in 22 (76%) patients (p<0.001; ). Fourteen (48%) patients had complete suppression of ventricular arrhythmias (including seven patients without any VPB), and 8 (28%) had partial suppression. None of the patients experienced significant (ie, couplet or VT) worsening of the exercise-induced ventricular arrhythmia score ().
Figure 1 Ventricular arrhythmia score per patient at the baseline exercise test on standard therapy and at the first exercise test on the final (stable) flecainide dose in the entire cohort (n=29; panel A), and in the patients who were treated with a first-line (more ...)
Flecainide treatment also significantly improved all other predefined parameters of exercise-induced ventricular arrhythmia (). For example, patients on flecainide achieved significantly higher heart rates before ventricular ectopy occurred. Independently, flecainide caused a significant reduction in maximum sinus rate during exercise, even though a higher mean workload was achieved. As expected (28
), flecainide prolonged the PR interval (149±21 vs. 160±24 ms; p=0.003), and the QRS duration (83±9 vs. 89±11 ms; p=0.005), but did not change the QTc interval (399±26 vs. 405±19 ms; p=0.171) at rest. These parameters remained within the normal range at rest and during peak exercise in all patients, except for a slightly prolonged resting PR interval (220 ms) in one patient (#20).
Exercise test results at the baseline exercise test on standard therapy and at the first exercise test on the final (stable) flecainide dose
We next assessed the reproducibility of exercise testing as a measure of the ventricular arrhythmia burden in CPVT. While not available for all patients, a subset of patients underwent repeated exercise testing either on the same dose of conventional therapy (n=14), or on the same flecainide dose (n=16). In both cases, the ventricular arrhythmia score of the second exercise test was not statistically different from that of the first exercise test (). Similarly, all other predefined parameters of exercise-induced ventricular arrhythmia also did not change significantly (e.g., the maximum number of VPBs during a 10-seconds period was 5±5 at the first exercise test on the stable flecainide dose, and 6±6 at the second exercise test on the same flecainide dose (p=0.556)), suggesting that ventricular arrhythmia scores obtained from exercise testing are reproducible measures of drug efficacy in CPVT and that tachyphylaxis was not present.
Ventricular arrhythmia score per patient at the baseline exercise test and at the previous exercise test on the same standard therapy dose (panel A), and at the first and second exercise test on the final (stable) flecainide dose (panel B)
We found that 14 of the 29 patients included in the primary analysis received drug therapy that could be considered suboptimal (i.e., an unusual β-blocker for CPVT (bisoprolol, carvedilol, or sotalol) or a relatively low β-blocker dose (atenolol, metoprolol, or nadolol <1 mg per kg body weight daily) (2
). These patients had either side effects on other β-blockers and/or a higher β-blocker dose, or nadolol was not available in their country. To assess whether flecainide was also effective in CPVT patients on optimal conventional therapy, we next analyzed the 15 patients who were treated with a first-line β-blocker at an optimal dose (). Flecainide significantly improved the ventricular arrhythmia score (p=0.003; ), and all other predefined arrhythmia parameters in this subgroup to a similar extent as in the primary analysis.
The ventricular arrhythmia score in the two patients (#7 and #30) who did not receive β-blocker therapy when flecainide was started improved from NSVT to couplet, and from NSVT to bigeminal VPBs and frequent VPBs, respectively.
Flecainide dose in CPVT
To estimate the optimal dosing of flecainide in CPVT, we analyzed the relationship between starting dose and VT suppression during the first exercise test on flecainide. Patients without suppression of exercise-induced ventricular arrhythmias on the starting flecainide dose received a significantly lower dose (113±39 mg; n=13; p=0.038) compared to patients with either partial (142±38 mg, n=6) or complete ventricular arrhythmia suppression (150±60 mg, n=12). Eight (24%) patients received an increased flecainide dose after the initial exercise test (). The dose increased from an average daily dose of 96±28 mg to 178±78 mg (range 100 to 300 mg), which resulted in a significant improvement in exercise-induced ventricular arrhythmia score ().
Dose-dependence of flecainide in eight CPVT patients who had an increase inflecainide dose
Three patients (#13, #30 and #31) discontinued flecainide with less than six months of follow-up due to side effects. One patient (#6) required a pacemaker because flecainide exacerbated pre-existing sinus node dysfunction. Flecainide was resumed after pacemaker implantation and this patient was included in the study. In two patients (#7 and #28) the stable flecainide dose was decreased because of dizziness. All other patients tolerated flecainide well without severe side effects. The β-blocker dose was reduced in five patients (#4, #5, #6, #9, and #12) who had a partial suppression of ventricular arrhythmias on flecainide and suffered from side effects of β-blocker therapy (in particular fatigue) before flecainide was started. One patient (#29) refused to take beta-blockers during follow-up, with no worsening of exercise-induced ventricular arrhythmias on flecainide monotherapy.
Thus, 30 out of 33 (91%) patients continued to receive flecainide and were included in the further analysis on the incidence of arrhythmic events. During a median follow-up of 20 months (range 12 to 40 (excluding patient 32#)), VT recurred in only one patient (#1) who experienced several appropriate ICD shocks for polymorphic VT after eight months of flecainide treatment. Her serum flecainide levels were low (0.34 mcg/mL) at the time of the event compared to levels obtained previously (0.75 to 0.82 mcg/mL), suggesting non compliance. She was hospitalized for 48 hours, nadolol and flecainide were resumed at their previous doses, and no further ventricular arrhythmias occurred during a further follow-up of 17 months. The other 29 patients have remained free of arrhythmic events during follow-up. The longest follow-up of 29 years was achieved in patient #32 who presented with exercise-induced VT in 1981. After unsuccessful trials of multiple antiarrhythmic drugs (including mexilitine, amiodarone, propranolol, sotalol, and Ca2+ channel blockers), flecainide (200 mg daily) was added to sotalol (160 mg daily), which resulted in complete suppression of ventricular arrhythmia during exercise testing. Subsequent genotyping revealed a mutation in RYR2. In 2008, an exercise test 48 hours after stopping flecainide and sotalol showed NSVT. After restarting the combined therapy, a subsequent exercise test only showed isolated VPBs, but no VT. In patient #33 flecainide 150 mg daily was started in 2007 because of two syncopes with ventricular fibrillation on the ICD interrogation despite nadolol 240 mg daily. Exercise testing showed complete suppression of ventricular arrhythmias and she has been free from arrhythmic events on flecainide for 40 months.