Author + information
- Received November 27, 2010
- Revision received December 17, 2010
- Accepted January 3, 2011
- Published online May 31, 2011.
- Christian van der Werf, MD⁎,
- Prince J. Kannankeril, MD, MSCI‡,
- Frederic Sacher, MD∥,
- Andrew D. Krahn, MD¶,
- Sami Viskin, MD#,
- Antoine Leenhardt, MD⁎⁎,
- Wataru Shimizu, MD, PhD††,
- Naokata Sumitomo, MD‡‡,
- Frank A. Fish, MD‡,
- Zahurul A. Bhuiyan, MD, PhD†,
- Albert R. Willems, MD, PhD⁎,
- Maurits J. van der Veen, MD, PhD§§,
- Hiroshi Watanabe, MD, PhD∥∥,
- Julien Laborderie, MD¶¶,
- Michel Haïssaguerre, MD∥,
- Björn C. Knollmann, MD, PhD§,⁎ ( and )
- Arthur A.M. Wilde, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Arthur A. M. Wilde, Academic Medical Center, University of Amsterdam, Department of Cardiology, Heart Failure Research Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- ↵⁎Dr. Björn C. Knollmann, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Division of Clinical Pharmacology, Medical Research Building IV, Room 1265, 2215B Garland Avenue, Nashville, Tennessee 37232-0575
Objectives This study evaluated the efficacy and safety of flecainide in addition to conventional drug therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).
Background CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca2+ release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca2+ channel blockers. The antiarrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca2+ release and triggered beats in vitro.
Methods We collected data from every consecutive genotype-positive CPVT patient started on flecainide at 8 international centers before December 2009. The primary outcome measure was the reduction of ventricular arrhythmias during exercise testing.
Results Thirty-three patients received flecainide because of exercise-induced ventricular arrhythmias despite conventional (for different reasons, not always optimal) therapy (median age 25 years; range 7 to 68 years; 73% female). Exercise tests comparing flecainide in addition to conventional therapy with conventional therapy alone were available for 29 patients. Twenty-two patients (76%) had either partial (n = 8) or complete (n = 14) suppression of exercise-induced ventricular arrhythmias with flecainide (p < 0.001). No patient experienced worsening of exercise-induced ventricular arrhythmias. The median daily flecainide dose in responders was 150 mg (range 100 to 300 mg). During a median follow-up of 20 months (range 12 to 40 months), 1 patient experienced implantable cardioverter-defibrillator shocks for polymorphic ventricular arrhythmias, which were associated with a low serum flecainide level. In 1 patient, flecainide successfully suppressed exercise-induced ventricular arrhythmias for 29 years.
Conclusions Flecainide reduced exercise-induced ventricular arrhythmias in patients with CPVT not controlled by conventional drug therapy.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited arrhythmia syndrome characterized by physical or emotional stress-induced bidirectional or polymorphic ventricular tachycardia (VT) in structurally normal hearts, with a high fatal event rate in untreated patients (1–3). Approximately 60% of CPVT patients have mutations in genes encoding the cardiac ryanodine receptor Ca2+ release channel (RyR2) or cardiac calsequestrin (4–6), and these cause spontaneous RyR2 channel openings (7,8). The resulting increase in cytosolic Ca2+ triggers delayed afterdepolarizations, ventricular premature beats (VPBs), and ventricular tachycardia, especially under conditions of β-adrenergic stimulation (9,10).
Hence, β-blockers are considered first-line therapy, but unfortunately they are not completely effective in preventing life-threatening arrhythmias (1–3,11–16). An implantable cardioverter-defibrillator (ICD) is often used in patients who continue to have ventricular arrhythmias despite β-blocker therapy. However, ICDs are not fully protective and can be proarrhythmic in CPVT patients because both appropriate and inappropriate ICD shocks can trigger catecholamine release, subsequently resulting in multiple shocks (arrhythmic storm), and death (17,18). Thus, additional therapy is desired for CPVT. Small case series show that left cardiac sympathetic denervation is effective in patients who are insufficiently protected by β-blocker therapy and/or experiencing too many ICD shocks (19–22).
Recently, we discovered that the antiarrhythmic agent flecainide directly blocks RyR2 channels, prevents RyR2-mediated premature Ca2+ release, and suppresses triggered beats in myocytes isolated from mouse hearts lacking calsequestrin, an animal model of CPVT (23). This effect is not mediated by Na+-channel block, the conventional mode of action thought to underlie flecainide activity, but rather can be attributed to open state block of RyR2 channels (that is, flecainide directly targets the molecular defect responsible for the arrhythmogenic Ca2+ waves that trigger CPVT in vivo) (24). In preliminary work, flecainide also appeared to be effective in 2 highly symptomatic CPVT patients (23).
Here we collate the data from every CPVT patient started on flecainide at 8 international centers and report on the efficacy and safety of flecainide treatment in CPVT.
Participants and study design
To better understand the efficacy and safety of flecainide in CPVT, we reviewed the chart of each consecutive CPVT patient in whom flecainide was started at 8 tertiary referral centers in the Netherlands, Canada, France, Israel, Japan, and the United States before December 2009. All patients had a clinical diagnosis of CPVT (based on exercise-induced bidirectional or polymorphic VT in the absence of structural cardiac disease) and a putative pathogenic mutation in the gene encoding RyR2 or cardiac calsequestrin. Determination of flecainide starting dose and dosing increases were made by the treating physician as part of specialized clinical care. Data collection and analysis were done retrospectively by chart review and were approved by the institutional review board at each participating institution.
Primary and secondary outcome measures
Couplets or VT during exercise are significantly associated with future arrhythmic events in CPVT (2). Because all patients were monitored by repeat exercise testing as part of routine clinical care, we used the reduction of ventricular arrhythmias during exercise testing as the primary outcome measure. The effect of flecainide was quantified by comparing the ventricular arrhythmia score (see later text) of the last exercise test on conventional therapy with the ventricular arrhythmia score of the first exercise test after a minimum of 5 days on the stable flecainide dose. Only patients on an unchanged or lower β-blocker dose during flecainide treatment were included in the primary analysis. Depending on the site, exercise testing was performed using a treadmill (standard or modified Bruce protocols) or bicycle ergometer.
Secondary outcome measures were the incidence of arrhythmic events (defined as syncope, aborted cardiac arrest, appropriate ICD shocks, and sudden cardiac death), assessment of well-being and side effects of flecainide, and monitoring of proarrhythmic effects of flecainide, in particular QRS duration during exercise and increase in the ventricular arrhythmia burden (25,26).
Definitions of ventricular arrhythmia
Exercise testing was analyzed and scored using the following pre-defined parameters (modified from Rosso et al. ): 1) ventricular arrhythmia score, defined by the worst ventricular arrhythmia (1, no or isolated VPBs; 2, bigeminal VPBs and/or frequent VPBs [>10 per min]; 3, couplet; and 4, nonsustained ventricular tachycardia [NSVT], ≥3 successive VPBs); 2) the presence of either of the parameters of the ventricular arrhythmia score or the presence of bidirectional VT (>3 successive VPBs with a beat-to-beat alternating right and left QRS axis); 3) sinus rate at the onset of ventricular arrhythmias, most often an isolated VPB; 4) maximum number of VPBs during a 10-s period; and 5) ratio of VPBs to sinus beats during the 10-s period with the maximum number of VPBs.
Reaching a ventricular arrhythmia score of 1 was considered complete suppression of ventricular arrhythmias. Other ventricular arrhythmia score improvements were considered partial suppression.
Continuous data are presented as mean ± SD or median (range), and categorical variables as number (percentage). Related samples were compared using the paired Wilcoxon signed-rank test for continuous and ordinal variables and the McNemar test for dichotomous variables. Independent continuous variables were compared by means of the Mann-Whitney U test. A 2-tailed p value <0.05 was considered statistically significant. Statistical analysis was performed with SPSS software package, version 15.0 (SPSS, Inc., Chicago, Illinois).
A total of 33 genotype-positive CPVT patients from 21 families were started on flecainide at 8 tertiary care centers (Table 1). All patients had persistent physical or emotional stress-induced ventricular arrhythmias documented by exercise testing, Holter recordings, or ICD interrogation and/or persistent symptoms of palpitations, syncope, aborted cardiac arrest, or appropriate ICD shocks, while taking β-blockers with or without Ca2+-channel blockers. Twenty-four of the patients (73%) were female. The median age at the start of flecainide therapy was 25 years (range 7 to 68 years). Thirty-one patients (94%) were treated with β-blockers, and 4 (12%) of them also received Ca2+-channel blockers (Table 1).
In 1 patient (Patient #13), flecainide was stopped because of side effects before exercise testing could be repeated; in another patient (Patient #27) the β-blocker dose was increased during flecainide treatment; and 2 patients (Patients #7 and #30) did not receive β-blocker therapy when flecainide was started (Table 1). 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 patients (59%), baseline exercise testing was performed <48 h before flecainide initiation.
Flecainide therapy reduces exercise-induced ventricular arrhythmias
Flecainide treatment improved the ventricular arrhythmia score in 22 patients (76%) (p < 0.001) (Fig. 1A). Fourteen patients (48%) had complete suppression of ventricular arrhythmias (including 7 patients without any VPBs), and 8 (28%) had partial suppression. None of the patients experienced significant (i.e., couplet or VT) worsening of the exercise-induced ventricular arrhythmia score.
Flecainide treatment also significantly improved all other predefined parameters of exercise-induced ventricular arrhythmia (Table 2). For example, patients receiving flecainide therapy achieved significantly higher heart rates before ventricular arrhythmias 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 ms vs. 160 ± 24 ms; p = 0.003), and the QRS duration (83 ± 9 ms vs. 89 ± 11 ms; p = 0.005), but did not change the QTc interval (399 ± 26 ms 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 1 patient (Patient #20).
We next assessed the reproducibility of exercise testing as a measure of the ventricular arrhythmia burden in CPVT. Although not available for all patients, a subset of patients underwent repeated exercise testing either at the same dose of conventional therapy (n = 14) or at the same flecainide dose (n = 16). In both cases, the ventricular arrhythmia score of the second exercise test was not statistically different from that on the first exercise test (Fig. 2). 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-s period was 5 ± 5 on the first exercise test at the stable flecainide dose and 6 ± 6 on the second exercise test at 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.
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/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 (Table 1). Flecainide significantly improved the ventricular arrhythmia score (p = 0.003) (Fig. 1B), and all other pre-defined arrhythmia parameters in this subgroup to a similar extent as in the primary analysis.
The ventricular arrhythmia score in the 2 patients (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 with patients with either partial (142 ± 38 mg, n = 6) or complete ventricular arrhythmia suppression (150 ± 60 mg, n = 12). Eight patients (24%) received an increased flecainide dose after the initial exercise test (Table 1). 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 the ventricular arrhythmia score (Fig. 3).
Three patients (Patients #13, #30, and #31) discontinued flecainide with <6 months of follow-up due to side effects. One patient (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 2 patients (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 decreased in 5 patients (Patients #4, #5, #6, #9, and #12) who had a partial suppression of ventricular arrhythmias on flecainide and experienced side effects of β-blocker therapy (in particular, fatigue) before flecainide was started. One patient (Patient #29) refused to take β-blockers during follow-up, with no worsening of exercise-induced ventricular arrhythmias on flecainide monotherapy.
Thus, 30 of 33 patients (91%) continued to receive flecainide and were included in the further analysis of the incidence of arrhythmic events. During a median follow-up of 20 months (range 12 to 40 months, excluding Patient #32), VT recurred in only 1 patient (Patient #1) who experienced several appropriate ICD shocks for polymorphic VT after 8 months of flecainide treatment. Her serum flecainide level was low (0.34 μg/ml) at the time of the event compared with levels obtained previously (0.75 to 0.82 μg/ml), suggesting noncompliance. She was hospitalized for 48 h, 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 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/day) was added to sotalol (160 mg/day), which resulted in complete suppression of ventricular arrhythmia during exercise testing. In 2008, an exercise test 48 h after stopping flecainide and sotalol showed NSVT. After restarting the combined therapy, a subsequent exercise test only showed isolated VPBs, but no VT. Subsequent genotyping revealed a mutation in the gene encoding RyR2. In Patient #33, flecainide 150 mg/day was started in 2007 because of 2 episodes of syncope with ventricular fibrillation on the ICD interrogation despite nadolol 240 mg/day. Exercise testing showed complete suppression of ventricular arrhythmias, and she has been free of arrhythmic events on flecainide for 40 months.
Our study demonstrates that flecainide reduces or prevents exercise-induced ventricular arrhythmias in the majority of CPVT patients receiving conventional drug therapy. These findings are important because several studies have demonstrated a significant failure rate of current drug therapy (1,3,11–16), including potentially fatal arrhythmic events in 11% of CPVT patients over an 8-year period (2). Based on our clinical experience reported here, flecainide in addition to β-blocker therapy should be considered for CPVT patients who otherwise have few alternative therapeutic options. The optimal dose appears to be between 150 and 200 mg/day (range 100 to 300 mg/day). Daily doses <100 mg were associated with a lack of therapeutic response.
Rationale for use of flecainide
CPVT is caused by mutations in the genes encoding RyR2 and cardiac calsequestrin (4,5), 2 proteins that control Ca2+ release from the sarcoplasmic reticulum. As a result of the mutations, Ca2+ is released prematurely and excessively into the cytosol under conditions of catecholaminergic stimulation, generating repetitive spontaneous Ca2+ waves (9,29). The increase in intracellular Ca2+ in turn activates the electrogenic Na+/Ca2+ exchanger, which produces a transient inward current (ITi). ITi generates delayed afterdepolarizations, which can lead to triggered activity, and the initiation of ventricular arrhythmias (30). Flecainide directly targets the molecular defect in CPVT by inhibiting RyR2 channels and preventing arrhythmogenic Ca2+ waves (23,24). Flecainide's Na+-channel blockade further reduces the rate of triggered beats (23,24). This dual action could explain why flecainide is so effective in severe CPVT and provides a rationale for combination therapy with β-blockers.
RyR2-mediated sarcoplasmic reticulum Ca2+ release importantly regulates the beating rate of sinoatrial nodal cells (31), especially in response to catecholamines (32), and flecainide reduces the rate of spontaneous sarcoplasmic reticulum Ca2+ release in myocytes (24). This mechanism may explain why maximum hearts rates were significantly lower in flecainide-treated patients even though workloads were higher compared with baseline exercise testing (Table 2). The reduction in sinus rate during exercise may further contribute to flecainide's efficacy in CPVT.
Given the high fatality rate of untreated CPVT patients (1,2), adequate treatment is mandatory and potentially life-saving. β-blockers are considered first-line therapy. In the largest published series of patients with CPVT, the risk of cardiac arrest (defined as aborted cardiac arrest, appropriate ICD shocks, and sudden cardiac death), despite β-blocker therapy during a mean follow-up period of 8 years, was 11% (2). Others have reported very diverse fatal or near-fatal event rates despite β-blocker therapy (1,3,11–16), although the highest event rates may be explained by the predominance of (symptomatic) probands and underdosing of β-blockers. An ICD was recommended for CPVT patients who were survivors of cardiac arrest, or when syncope or sustained VT persisted despite maximum tolerable β-blockade (33). Yet, ICDs have a potentially harmful effect in CPVT patients (17,18). Moreover, many CPVT patients are children, in whom ICD implantation can lead to significant complications (34). Thus, to avoid ICD implantation and prevent ICD shocks in patients with ICDs, controlling ventricular arrhythmias is of great clinical importance. Alternative therapies are needed for CPVT patients.
Left cardiac sympathetic denervation is an effective alternative when symptoms persist despite β-blockade, but requires surgery, is not universally available, and has only been tested in small cohorts (19–22). The use of Ca2+-channel blockers in addition to β-blockade has been reported to decrease ventricular ectopy in CPVT patients with continuous symptoms and/or exercise-induced ventricular arrhythmias (12,27,35), but is not effective in all patients (27,35,36). From the original 6 patients treated with verapamil and β-blockers after failure of β-blockers alone, reported by Rosso et al. (27) in 2007, 3 had clinically significant ventricular arrhythmias during 37 ± 6 months of follow-up (36). Other pharmacological agents, including Na+-channel blockers, amiodarone, and magnesium, lack of efficacy in CPVT patients (1,12).
In this analysis of all consecutive patients started on flecainide at 8 international centers, adding flecainide to standard therapy was effective in further reducing exercise-induced VT and preventing arrhythmic events CPVT patients. To suppress CPVT, adequate dosing of flecainide seems critical. An increased dose may be effective when the initial dose of flecainide fails to suppress VT. Based on these results, flecainide could be added to β-blocker therapy when symptoms or either spontaneous or exercise-induced ventricular arrhythmias persist despite β-blocker.
In our young patient population with no structural heart disease, the proarrhythmic effect of flecainide as documented in patients with ischemia and impaired left ventricular function (37) may not be applicable. Consistent with this hypothesis, flecainide did not cause arrhythmic events during a median follow-up of 20 months, which is longer than the mean follow-up of 10 months in the CAST (Cardiac Arrhythmia Suppression Trial). The only arrhythmic event was associated with low flecainide serum levels, suggesting that the event was due to the underdosing and not toxicity.
This study reports on our experience of using flecainide in a clinical setting. The number of patients is relatively small because CPVT is a rare condition and only patients without other treatment alternatives were started on flecainide. However, it is the largest evaluation of a new therapeutic strategy in CPVT patients refractory to current drug therapy, with a median of 20 months follow-up. One patient has received flecainide for 29 years with continuous VT suppression on unchanged doses, and another severely symptomatic patient has been free of arrhythmic events on flecainide for 40 months. Nevertheless, long-term follow-up in more patients would further support the clinical utility of flecainide in CPVT.
Another potential limitation is that we only quantified the effect of flecainide on exercise-induced ventricular arrhythmias, which may not accurately predict fatal arrhythmic events. However, exercise testing is clinically used to guide therapy in CPVT. In a previous study including 70 CPVT patients, exercise-induced couplets or more successive VPBs were significantly associated with future arrhythmic events (sensitivity, 0.62; specificity, 0.67) (2).
Furthermore, we cannot exclude potential bias introduced by the variability of exercise test results on unchanged treatment, as illustrated in Figure 2. Finally, in 14 patients, conventional therapy may be considered suboptimal because they received an unusual β-blocker for CPVT or a low β-blocker dose for reasons previously outlined. However, flecainide was equally effective in the subgroup of CPVT patients who were treated with a first-choice β-blocker at an adequate dose (Fig. 1B).
Our results suggest that flecainide is a safe and effective therapy to reduce ventricular arrhythmias in the majority of CPVT patients who have exercise-induced ventricular arrhythmias despite conventional therapy.
This work was supported by ZorgOnderzoek Nederland Medische Wetenschappen (ZonMW, grant 120610013 to Drs. van der Werf and Wilde), by the U.S. National Institutes of Health (grants HL88635, HL71670 to Dr. Knollmann and HL076264 to Dr. Kannankeril), by a grant from the Heart and Stroke Foundation of Ontario (grant NA3397 to Dr. Krahn), by a grant from the French national government named Programme Hospitalier de Recherche Clinique (grant AOR04070, P040411 to Dr. Leenhardt), by a Research Grant for Cardiovascular Diseases (21C-8) from the Ministry of Health, Labor, and Welfare, Japan (to Dr. Shimizu), by the American Heart Association Established Investigator Award (grant 0840071N to Dr. Knollmann), and by the Fondation Leducq Trans-Atlantic Network of Excellence, Preventing Sudden Death (grant 05-CVD-01 to Dr. Wilde). Dr. Leenhardt is a consultant to Sanofi-Aventis and MedaPharma. Dr. Wilde is on the Advisory Board of PGX Health. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- catecholaminergic polymorphic ventricular tachycardia
- implantable cardioverter-defibrillator
- nonsustained ventricular tachycardia
- cardiac ryanodine receptor Ca2+ release channel
- ventricular premature beat
- ventricular tachycardia
- Received November 27, 2010.
- Revision received December 17, 2010.
- Accepted January 3, 2011.
- American College of Cardiology Foundation
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