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

Andreas Rillig; Lars Eckardt; Katrin Borof; A John Camm; Harry J G M Crijns; Andreas Goette; Günter Breithardt; Marc D Lemoine; Andreas Metzner; Laura Rottner; Ulrich Schotten; Eik Vettorazzi; Karl Wegscheider; Antonia Zapf; Hein Heidbuchel; Stephan Willems; Larissa Fabritz; Renate B Schnabel; Christina Magnussen; Paulus Kirchhof

doi:10.1093/europace/euae121

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

Europace. 2024 Jun 3;26(6):euae121. doi: 10.1093/europace/euae121.

Authors

Andreas Rillig^{1

2}, Lars Eckardt^{3

4}, Katrin Borof¹, A John Camm⁵, Harry J G M Crijns⁶, Andreas Goette^{3

7

8}, Günter Breithardt^{3

4}, Marc D Lemoine^{1

2}, Andreas Metzner^{1

2}, Laura Rottner^{1

2}, Ulrich Schotten⁹, Eik Vettorazzi¹⁰, Karl Wegscheider^{2

3

10}, Antonia Zapf¹⁰, Hein Heidbuchel^{11

12

13}, Stephan Willems¹⁴, Larissa Fabritz^{1

2

3

15

16}, Renate B Schnabel^{1

2

3}, Christina Magnussen^{1

2}, Paulus Kirchhof^{1

2

3

16}

Affiliations

¹ Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
² German Center for Cardiovascular Research, Partner Site Hamburg/Luebeck/Kiel, Germany.
³ Atrial Fibrillation Network (AFNET), Mendelstraße 11, 48149 Münster, Germany.
⁴ Department of Cardiology II-Electrophysiology, University Hospital Münster, Münster, Germany.
⁵ Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's University of London, London, UK.
⁶ Department of Cardiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
⁷ St. Vincenz Hospital, Paderborn, Paderborn, Germany.
⁸ Working Group of Molecular Electrophysiology, University Hospital Magdeburg, Magdeburg, Germany.
⁹ Department of Physiology, Maastricht University, Maastricht, The Netherlands.
¹⁰ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Faculty of Medicine and Health Sciences, Department of Cardiology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
¹² Faculty of Medicine and Health Sciences, Cardiovascular Research, GENCOR, Antwerp University, Antwerp, Belgium.
¹³ Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.
¹⁴ Asklepios Klinik St. Georg, Klinik für Kardiologie und internistische Intensivmedizin, Hamburg, Germany.
¹⁵ University Center of Cardiovascular Science, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.

Abstract

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.

Keywords: Atrial fibrillation; Coronary artery disease; Early rhythm control; Heart failure; Sodium channel blocker; Stable cardiovascular disease.

Publication types

Multicenter Study
Randomized Controlled Trial

MeSH terms

Aged
Anti-Arrhythmia Agents* / adverse effects
Anti-Arrhythmia Agents* / therapeutic use
Atrial Fibrillation / drug therapy
Female
Flecainide* / adverse effects
Flecainide* / therapeutic use
Heart Failure / drug therapy
Heart Failure / physiopathology
Heart Rate / drug effects
Humans
Male
Middle Aged
Sodium Channel Blockers* / adverse effects
Sodium Channel Blockers* / therapeutic use
Stroke
Time Factors
Treatment Outcome

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

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