Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial.

Aims: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4.
Methods and Results: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)].
Conclusion: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.
Competing Interests: Conflict of interest: A.R.: Consultant fees, travel grants or lecture fees from Medtronic, Biosense Webster, Abbott, Boston Scientific, Ablamap, Philips, Cardiofocus, Bayer, Pfizer and Novartis, Edwards and Lifetech. Committee: German Society of Cardiology (Select-chair of EP community). L.E.: Grants/contracts: research support by the German heart foundation. Consulting fees Boston Scientific, lecture fees for various medical companies. Society, committee: German Society of Cardiology; European Society of Cardiology; European Heart Rhythm Society. K.B.: no COIs. J.C.: Participation on a data safety monitoring board: Anthos, Johnson and Johnson, Enso, Bayer, Charité. H.C.: Grants/contracts: ZonMw grant no. 104021005 RACE 9 Device-based rate vs. rhythm control treatment in patients with symptomatic recent-onset atrial fibrillation in the emergency department (RACE 9). Consulting fees: InCarda Therapeutics, Roche, Sanofi, Atricure. Payment or Honoraria: Medtronic. Participation on a data safety monitoring board or advisory board: Chair DSMB Decision trial. Committee/society: DZHK, German Centre for Cardiovascular research. A.G.: Grants/contracts: Maestria Grant EU 965286. Consulting fees: Sanofi-Aventis, Bayer, Astra Zeneca, Daiichi Sankyo, BMS/Pfizer, Viofor, Boston Scientific, Medtronic, Menarini. G.B.: Chair, advisory board to AFNET e.V., no payment. M.L.: No COIs. A.M.: Consulting fees: Medtronic, Johnson and Johnson, Boston Scientific, LifeTech. Lecture honoraria: Medtronic, Johnson and Johnson, Lifetech, Pfizer, Boston Scientific, Bayer, Bristol Meyer Squibb. L.R.: No COIs. U.S.: Grants/contracts: EU: CATCH ME, MAESTRIA, Personalize AF, REPAIR, Dutch Heart foundation, RACE V Embrace. Consulting fees: Roche advisory board, YourRhythmics BV. Payment or honoraria: Johnson and Johnson. Patents: non-invasive classification of AF with ECG. Society/Committee: Board of directors of AFNET. Stock or stock options: YourRhythmics BV. E.V.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. K.W.: All support payment for manuscript: AFNET. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific, Novartis. A.Z.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific. H.H.: Unconditional Research Grants through the University of Hassels and Antwerp: Abbott, Medtronic, Biotronik, Boston scientific, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer–BMS. Payment or honoraria: Bayer, Biotronik, Bristol Myers Squibb, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, CTI Germany, European Society of Cardiology, Medscape, Springer healthcare. Participation on a data safety monitoring board or advisory board: Member, DSBM Prestige-AF. S.W.: Grants: Boston Scientific, Consulting fees: Boston Scientific, Abbott. Speakers Bureau: BSCI; Abbott, BMS, Medtronic. L.F.: Institutional government or charity research support: European Union Horizon 2020 MAESTRIA [grant agreement number 965286 (MAESTRIA)] European Union Horizon 2020 CATCH ME, [grant agreement number 633196 (CATCH ME), European Union Horizon 2020 AFFECT-EU, grant agreement number 847770 (AFFECT-EU)] Institutional governmental support, National Institute for Health and Care Research NIHR, Medical Research Council (UK), German Centre for Cardiovascular Research DZHK. Support for attending meetings: ESC, EHRA, and ESC working groups, ARVC patient organization (charity). Patents planned issued or pending: L.F. is listed as inventor of two patents (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Society/committee: BHF project grant committee (charity). BHF chair committee visits (charity), AFNET steering committee (charity), ARVC patient organization (charity). Equipment and analytics to AFNET for AFNET 9: Preventicus, Trial costs to AFNET for AFNET 9: Daiichi Sankyo. R.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). Wolfgang Seefried project funding German Heart Foundation. Lecture fees and advisory board fees from BMS/Pfizer and Bayer. Society/committee: ESC stroke council nucleus member. C.M.: Grants or contracts: Research funding from German Center for Cardiovascular Research (Promotion of women scientists programme; FKZ 81X3710112); Deutsche Stiftung für Herzforschung; Dr. Rolf M. Schwiete Stiftung; NDD; Loewenstein Medical. Payment or honoraria: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, Abbott. Support for attending meetings: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Novo Nordisk. Participation on a data safety monitoring board or advisory board: Boehringer Ingelheim/Lilly; Novo Nordisk. P.K.: P.K. was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/17/30/32961; PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation. P.K. is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is board member of the ESC and speaker of the board AFNET.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)