A Prospective, Multi-Center, Randomized, Open Label Trial to Determine if a Common Atrial Fibrillation Risk Locus Modulates Differential Response to Antiarrhythmic Drugs

1.0 Background

While atrial fibrillation (AF) is the most common sustained cardiac arrhythmia requiring therapy, it is also associated with increased risk of stroke, heart failure, myocardial infarction, dementia, and death. The number of Americans affected with AF is expected to surge to nearly 16 million by the year 2050. The AF epidemic may in part be related to the aging of the population and increasing prevalence of recently identified risk factors including obesity, metabolic syndrome, obstructive sleep apnea, and inflammation. Furthermore, there is increasing support for the idea that both common and rare genetic variants also increase susceptibility to AF which can clinically manifest in the presence of acquired risk factors. While clinical risk factors for AF are established, the genetic components of this "multiple-hit" genetic model for the development of AF have only recently been identified.

Despite recent advances in catheter-based and surgical therapies, anti-arrhythmic drugs (AADs) remain the mainstay of treatment for patients with symptomatic AF. However, response in an individual is highly variable with more than half of patients treated with AADs suffering a recurrence of AF within 6 to 12 months. The limited success of therapy for AF is related to poor understanding of the underlying pathophysiology, heterogeneity of the electrical and structural substrate, and the lack of targeted mechanism-based therapies. Thus, one major knowledge gap is predicting response to AADs in an individual patient. Contemporary membrane-active drugs used to suppress AF are incompletely and unpredictably effective and are associated with significant risks of proarrhythmia and non-cardiac toxicities. Furthermore, the current 'one-size fits all' approach to selecting AAD therapy for a patient with symptomatic AF is based largely on minimizing the risk of adverse events rather than on the likelihood of efficacy. Recent advances in our understanding of genetic mechanisms of AF support the overarching hypothesis we wish to test in future studies that variability in response to AAD therapy is modulated by common genetic variants associated with AF. Several AF susceptibility loci have been identified and validated in genome-wide association studies. In addition, we have shown that common AF risk single nucleotide polymorphisms (SNPs) at the chromosome (chr) 4q25 locus not only predict poor response to AADs but also recurrence of AF after ablation therapy and cardioversion.

While genetic approaches to AF have revealed that susceptibility to AF and response to therapy are modulated in part by the underlying genetic substrate, the translation of these discoveries to the bedside management of AF patients has thus far been limited. This relates to poor understanding of the underlying mechanisms associated with common AF risk alleles, challenges associated with determining efficacy of AADs and lack of genotype-directed prospective studies. Our preliminary data showed that a common chr4q25 SNP associated with AF predicted successful symptom control in patients treated with AADs and individuals who carried the risk variant responded better to Vaughan Williams class I vs. class III AADs. Based on the information collected in this feasibility and pilot study, we propose to conduct a prospective pharmacogenomic study where a cohort of patients with frequent symptomatic paroxysmal AF will be randomized to a flecainide (class I AAD) or sotalol (class III AAD) in order to determine if response to therapy is modified by chr4q25 SNPs using AF burden as a metric of drug efficacy. This main study, like the pilot study proposed here, will utilize a crossover design to minimize inter-individual variability and maximize statistical power to detect an interaction between chr4q25 genotype and the reduction of AF burden with flecainide vs. sotalol. After a run-in period during which the AAD will be up-titrated, subjects will be monitored with the Medtronic Reveal LINQ Insertable Cardiac Monitor (ICM) system to assess AF burden. Furthermore, subjects will be asked to complete a comprehensive, validated 20-item AF specific questionnaire (AF Effect on QualiTy-of-life [AFEQT]) at baseline, and monthly thereafter for the duration of the study. At the end of the 6-month trial period, the AAD will be discontinued and participants will be switched to the other AAD and followed for another 6-month period in a crossover trial design.

2.0 Rationale and Specific Aims