Pharmacogenetic Study of Antiarrhythmic Drugs for Atrial Fibrillation

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

We and others have shown common SNPs at the chr4q25 locus are associated with increased risk of AF and modulate symptomatic response to AADs. Furthermore, our preliminary data suggests that there is a differential response to class I vs. class III membrane-active drugs. Here, we propose a pilot study to obtain preliminary data regarding AF burden in patients receiving AADs and to demonstrate feasibility for a future study to test the hypothesis that chr4q25 risk SNPs modulate differential response to AADs in patients with frequent symptomatic paroxysmal AF using reduction in mean AF burden as a metric of drug efficacy. Therefore, the Specific Aim of this pilot/feasibility study is to obtain preliminary data regarding AF burden in patients receiving AADs and to demonstrate feasibility for a future study to test the hypothesis that chr4q25 SNPs modulate differential response to class I vs. class III AADs in patients with frequent symptomatic AF.

3.0 Previous Human Studies

Chr4q25 SNPs modulate differential response to AADs in patients with AF In a preliminary study we addressed whether symptomatic response to AAD therapy is modulated by the 3 common AF susceptibility loci on chr4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3). We studied 478 (discovery cohort) and 198 (validation cohort) age and gender matched Caucasian patients in the Vanderbilt AF Registry. Response to AAD therapy was defined as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥ 75% reduction in AF symptoms. Multiple clinical variables (including age, hypertension, lone AF) failed to predict response to AADs. However, a SNP at the 4q25 locus (rs10033464) was significantly associated with successful symptom control (odds ratio \[OR\] 2.97, 95% confidence interval \[CI\] 1.42-6.21, P=0.003). Furthermore, individuals who carried the 4q25 SNP responded better to class I vs. class III AADs in both the discovery and validation cohorts. These preliminary findings provide the rationale for our future studies by suggesting that common AF susceptibility variants differentially modify the response to class I vs. class III AADs in patients with frequent symptomatic AF.

4.0 Enrollment/Randomization

Patients ≥18 years of age with symptomatic paroxysmal AF will be enrolled from the Arrhythmia and Cardiology Clinics, the Adult Emergency Department, and inpatient Cardiology services at University of Illinois Medical Center. For patients with whom researchers do not have a relationship, introductions from a member of their care team will be sought prior to discussion of the study. After obtaining the permission of the patient, a member of the study team will explain the study, answer any questions, and allow sufficient time to be certain that the subject understands the study and has given their consent to participate. Consent will be documented by signing the informed consent document, a copy of which will be given to the subject.

5.0 Study Procedures

Randomization: Patients will be consented and randomized to either flecainide or sotalol for six months and then crossed-over to the alternate drug for six months, regardless of the efficacy of the first drug. Study randomization will be through http://www.randomize.net/. Each participating will have access to the randomization application and each site responsible per their local IRB regulations to maintain the randomization study list. The study will be open-label.

Baseline visit procedures: The baseline visit will take place at the AF and Cardiology Clinic at the Outpatient Care Center (OCC) of UIHHSS. This visit will involve reviewing eligibility and the consenting process. Patients will present to the OCC and be met by a study physician, who will perform a history and physical exam. A baseline 12-lead ECG will be obtained for all patients and interpreted by the study physician to verify eligibility. Patients who meet the criteria will be randomized into one of the two study medications (sotalol or flecainide), and scheduled by a study nurse to come back to UIHHSS within one week to receive the Medtronic Reveal ICM implantation and administered the initial dose of study drug.

For patients randomized to start sotalol first, they will be scheduled by the study nurse to return to UIH in approximately 1 week to be admitted for up to 72 hours, which is routinely done for sotalol administration. The designated cardiology/AF nurse will schedule this admission after the consenting/baseline visit is completed in the clinic. At the second visit, once inclusion and exclusion criteria are confirmed again for continued eligibility, a peripheral intravenous catheter will be placed, and blood will be drawn for a basic metabolic panel (BMP), particularly potassium (K+) and creatinine (Cr). This is routinely done for patients hospitalized for initiation of sotalol. The study physician will determine the initial sotalol dose (80 - 120mg twice a day by mouth) based on Cr CL.

Two hours after the first dose of study drug is given a 12-lead ECG will be recorded and interpreted by the study physician. If the QTc is \>500 msec, the sotalol dose will be reduced under the direction of the study physician. Patients will be admitted for continuous telemetric monitoring and will remain in UIH until the 5th dose is administered as long as the physician confirms eligibility with each dose. Additional 12-lead ECGs will be obtained two hours after the 3rd and 5th doses of sotalol to assess QTc duration. The BMP will also be drawn to routinely monitor the subject's K+ and Cr. If the QTc duration remains \>500 msec even after adjustment of the sotalol dose, the drug will be stopped and the patient will be excluded from the study. If the QTc remains ≤500 msec after the 5th dose of sotalol, the patient will be discharged to home.

Intravenous sotalol rapid initiation will be also available to study participants. Patients admitted to University of Illinois Hospital and Clinics (Hospital) to initiate treatment are admitted to the cardiology service and located on 6 West Step-Down or 7 East Step-Down nursing unit with continuous cardiac telemetry monitoring. See study addendum for intravenous sotalol rapid initiation clinical care guideline.

A phone call will be made by the study coordinator or study physician 3 days after discharge to check subject's status and ensure they are tolerating sotalol and are not experiencing any untoward side effects.

Patients randomized to flecainide at the baseline visit will initially be scheduled for follow up at the UIH Electrophysiology Laboratory within one week. At the second visit, once inclusion and exclusion criteria are confirmed again for continued eligibility, a LINQ ICM will be inserted. The patient will be observed for two hours after the ICM insertion. During this time, an ECG will be performed and a quality of life (QoL) questionnaire will be administered. After 2 hours of observation after ICM insertion, the 1st dose of flecainide will be administered (50-100mg at physician's discretion). As per guidelines for flecainide, subjects will also concomitantly be started on either beta blockers (25 mg by mouth once a day) or diltiazem (120 mg long-acting by mouth once a day) based on the patient's tolerability. An AV nodal blocker like beta blockers and diltiazem is often co-prescribed with flecainide to prevent the development of 1:1 conducted atrial flutter.

After

• AF Effect on QualiTy-of-life [AFEQT] [Срок оценки: 12 months]