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Christian van der Werf, MD, Prince J. Kannankeril, MD, MSCI,

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,

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Christian van der Werf, MD, Prince J. Kannankeril, MD, MSCI,

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  1. 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

  2. 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

  3. 1Hayashi et al. Circulation 2009 Conventionaltherapy in CPVT • First-line therapy: β-blocker • 8-year (near-)fatal event rate: 11%1 • Alternatives: • Ca2+-channel blocker • Not effective in all patients • Left cardiac sympathetic denervation • Effective, but requires surgery, not universally available, and only tested in small cohorts • Implantable cardioverter-defibrillator • Potentially harmful effect in CPVT patients

  4. Watanabe et al. Nat Med 2009 Flecainide in CPVT • Flecainide directly targets the molecular defect in CPVT • Blocks the RyR2 channel • Prevents RyR2-mediated premature Ca2+ release • Suppresses triggered beats (INa block) • Flecainide was effective in 2 highly symptomatic CPVT patients

  5. Participants and study design • 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

  6. Primary outcome measures • Ventricular arrhythmias during exercise testing • Ventricular arrhythmia score • None / isolated ventricular premature beats (VPB) • Bigeminal VPBs and/or frequent VPBs (>10/min) • Couplet • Non-sustained VT • Sinus rate at onset of ventricular arrhythmias • Max number of VPBs during worst 10 seconds • Stable β-blocker dose • Baseline vs. first exercise test on stable flecainide dose J Am Coll Cardiol 2011;57:2244-54

  7. Secondary outcome measures • Incidence of cardiac events • Side effects • Proarrhythmiceffects J Am Coll Cardiol 2011;57:2244-54

  8. Patient characteristics 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 J Am Coll Cardiol 2011;57:2244-54

  9. Conventional andflecainidetherapy • 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

  10. Ventricular arrhythmia score allpatients(n = 29) J Am Coll Cardiol 2011;57:2244-54

  11. Ventricular arrhythmia score patientswithoptimalconventionaltherapy (n = 15) J Am Coll Cardiol 2011;57:2244-54

  12. Other primaryoutcomemeasures J Am Coll Cardiol 2011;57:2244-54

  13. 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

  14. Dose-dependence of flecainide • Change in ventriculararrhythmia score in 8 patients in whom the flecainidedose was increasedafter the initialexercise test J Am Coll Cardiol 2011;57:2244-54

  15. Secondary outcome measures • 3 patients discontinued flecainide within 6 months due to side effects • One cardiac event during median follow-up of 20 [12-40] months • Several appropriate ICD shocks (associated with low flecainide levels)  no further events during 17-month follow-up • One patient free of arrhythmic events on flecainide and sotalol for 29 years • No worsening in ventricular arrhythmias • PR and QRS duration normal J Am Coll Cardiol 2011;57:2244-54

  16. 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

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