Flecainide Therapy Reduces Exercise-Induced Ventricular Arrhythmias in Patients With

Catecholaminergic Polymorphic Ventricular Tachycardia

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, FESC, Julien Laborderie, MD, Michel Haïssaguerre, MD,

Björn C. Knollmann, MD, PhD, Arthur A.M. Wilde, MD, PhD

Amsterdam and Ede, the Netherlands; Nashville, Tennessee; Bordeaux and Paris, France; London, Canada; Tel Aviv, Israel; and Suita, Tokyo and Niigata, Japan

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

Malignant inherited arrhythmia syndrome characterized by physical/emotional stress-induced polymorphic ventricular tachycardia (VT) in structurally normal hearts

Mutations in RyR2 (~60%) or CASQ2 (~2%)

J Am Coll Cardiol 2011;57:2244-54

Conventional therapy in CPVT

First-line therapy: β-blocker8-year (near-)fatal event rate: 11%1

Alternatives:Ca2+-channel blocker

Not effective in all patients

Left cardiac sympathetic denervationEffective, but requires surgery, not universally available, and

only tested in small cohorts

Implantable cardioverter-defibrillatorPotentially harmful effect in CPVT patients

1Hayashi et al. Circulation 2009

Flecainide in CPVT

Flecainide directly targets the molecular defect in CPVTBlocks the RyR2 channelPrevents RyR2-mediated premature Ca2+

releaseSuppresses triggered beats (INa block)

Flecainide was effective in 2 highly symptomatic CPVT patients

Watanabe et al. Nat Med 2009

Retrospective chart review of every CPVT patient started on flecainide before December 2009 at eight centers worldwide

Decisions on flecainide dose made by treating cardiologist

All patients positive for RYR2 or CASQ2 mutation

Ventricular arrhythmias during exercise testingVentricular arrhythmia score

I. None / isolated ventricular premature beats (VPB)II. Bigeminal VPBs and/or frequent VPBs (>10/min)III. CoupletIV. Non-sustained VT

Sinus rate at onset of ventricular arrhythmiasMax number of VPBs during worst 10 secondsStable β-blocker doseBaseline vs. first exercise test on stable flecainide

dose

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Incidence of cardiac events

Side effects

Proarrhythmic effects

J Am Coll Cardiol 2011;57:2244-54

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

VariableCPVT patients

(n = 33)

Age at diagnosis, years 18 [3-57]

Female 24 (73%)

RyR2 mutation 32 (97%)

Probands 15 (45%)

Symptomatic before diagnosis 21 (64%)

History of aborted cardiac arrest 4 (12%)

J Am Coll Cardiol 2011;57:2244-54

Conventional and flecainide therapy

VariableCPVT patients

(n = 33)

β-blocker at baseline 31 (94%)

Ca2+-channel blocker at baseline 4 (12%)

Implantable cardioverter-defibrillator 12 (36%)

Age at start of flecainide, years 25 [7-68]

Severe ventricular arrhythmias at baseline (≥2 consecutive VPBs)

26 (79%)

4 patients excluded from primary analysis (2 did not receive β-blocker, 1 discontinued flecainide, 1 received higher β-blocker dose in addition to flecainide)

Secondary analysis in 15 patients treated with first-line β-blocker at an optimal dose

J Am Coll Cardiol 2011;57:2244-54

Ventricular arrhythmia score all patients (n = 29)

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Ventricular arrhythmia score patients with optimal conventional therapy (n = 15)

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Other primary outcome measures

Variable

Standard therapy baseline (n = 29)

Flecainide therapy

test 1(n = 29)

p Value

Time after start flecainide, days - 21 [5-363] -

SR at baseline, bpm 57 ± 10 59 ± 9 0.061

SR at maximal exercise, bpm 145 ± 23 133 ± 18 0.002

Maximum workload attained, METS 11 ± 3 12 ± 4 0.042

SR at onset of ventricular arrhythmias, bpm

113 ± 19 118 ± 19 0.046

Max number of VPBs during 10s 12 ± 5 5 ± 5 <0.001

Non-sustained VT 11 (38%) 1 (3%) 0.002

Couplet 20 (69%) 2 (7%) <0.001

J Am Coll Cardiol 2011;57:2244-54

Variable

No suppression

(n=13)

Partial suppression

(n=6)

Complete suppression

(n=12)

P no vs.

partial/complete

Flecainide dose, mg

113 ± 39142 ± 38 150 ± 60 0.038

Dose-dependence of flecainide

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

J Am Coll Cardiol 2011;57:2244-54

Change in ventricular arrhythmia score in 8 patients in whom the flecainide dose was increased after the initial exercise test

Dose-dependence of flecainide

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3 patients discontinued flecainide within 6 months due to 3 patients discontinued flecainide within 6 months due to side effectsside effects

One cardiac event during median follow-up of 20 [12-40] One cardiac event during median follow-up of 20 [12-40] monthsmonths Several appropriate ICD shocks (associated with low flecainide Several appropriate ICD shocks (associated with low flecainide

levels) levels) no further events during 17-month follow-up no further events during 17-month follow-up

One patient free of arrhythmic events on flecainide and One patient free of arrhythmic events on flecainide and sotalol for 29 yearssotalol for 29 years

No worsening in ventricular arrhythmiasNo worsening in ventricular arrhythmias

PR and QRS duration normalPR and QRS duration normal

J Am Coll Cardiol 2011;57:2244-54

Conclusion

Flecainide was a safe and effective therapy that reduced ventricular arrhythmias in the majority of CPVT patients who had exercise-induced ventricular arrhythmias despite conventional therapy.

J Am Coll Cardiol 2011;57:2244-54