H558R: a common polymorphism may modify the efficacy and toxicity of flecainide in maintaining sinus rhythm; a cohort study

Abstract Background Certain mutations in the SCN5A gene alter the function of the type V voltage-gated cardiac sodium channel and the therapeutic effect of flecainide.(1) One such mutation, H558R, represents a polymorphism with a high prevalence associated with the development of atrial fibrillation (AF).(2–5) Purpose We aim to determine its relationship with the efficacy and adverse effects of flecainide, as well as describe for the first time its prevalence in a cohort of European patients with AF. Methods We conducted a cohort study collecting data through indirect methods, with the study being blinded to all parties involved except the statistician. Patients prescribed flecainide (dose of 100 mg/12 h) and followed up in our health area (n=450,000 people) between 2017 and 2021 were identified. A primary composite endpoint consisting of initial inefficacy and early toxicity and a secondary combined endpoint of toxicity or inefficacy during follow-up were predefined. Results Out of 104 patients who met the criteria and agreed to participate, 59 (56.4%) did not have the mutation (H558R-/-), 38 (36.5%) were heterozygous (H558R+/-), and 7 (6.7%) were homozygous (H558R+/+). This high prevalence in European patients with AF is significantly higher than that previously reported in healthy individuals (20.4% in Caucasians, 9.2% in Asians).(6) When compared with patients without the mutation, H558R+/- patients had a lower incidence of the primary endpoint (p=0.02, picture 1), with an absolute risk reduction (ARR) of -21.5% (95% confidence interval (CI): -38.4% to -4.6%) primarily due to a lower rate of initial inefficacy (ARR -18.35%, 95% CI: -1.37% to -35.3%), and a trend towards lower early toxicity (ARR -7.36; 95% CI: -19.9 to +5.2%). This difference remained in the multivariate analysis (p=0.03, table 1). Moreover, the H558R+/- genotype was associated with lower toxicity or inefficacy over an average follow-up of 492 days (p=0,04, picture 1), with a hazard ratio of 0.53 (95% CI: 0.27 to 0.999). Conclusions The H558R+/- mutation shows a marked prevalence in a selected sample of patients with AF. Its presence is clinically relevant both in terms of early efficacy or toxicity and during follow-up. If these results are confirmed, it may signify a step towards personalized treatment for patients with AF, not only from the standpoint of efficacy but also safety.Table 1.Picture 1.