Efficacy of Class I vs. Class III Antiarrhythmic Drugs in Obese Patients
By Joshua Moss, MD
Associate Professor of Clinical Medicine, Cardiac Electrophysiology, Division of Cardiology, University of California, San Francisco
Dr. Moss reports he is a consultant for Abbott, Biosense Webster, and Boston Scientific.
SYNOPSIS: In an observational cohort of patients with atrial fibrillation, obese patients were less likely than nonobese patients to avoid symptomatic recurrence on sodium channel blocking agents in contrast to a roughly equivalent response in both groups to potassium channel blocking agents.
SOURCE: Ornelas-Loredo A, Kany S, Abraham V, et al. Association between obesity-mediated atrial fibrillation and therapy with sodium channel blocker antiarrhythmic drugs. JAMA Cardiol 2020;5:57-64.
In a recent Mendelian randomization study, a causal relationship between obesity and atrial fibrillation (AF) was demonstrated. Emerging evidence implicates modulation of the cardiac sodium channel as a potential mechanism. However, little is known about whether obesity-related abnormalities in the cardiac sodium channel affect the response to class I (sodium channel blocking) antiarrhythmic drugs (AADs). Ornelas-Loredo et al conducted an observational cohort study of 311 adults with documented AF and attempted maintenance of sinus rhythm with either class I or class III AADs. Obesity was defined as a body mass index (BMI) > 30 kg/m2. Patients were deemed to have a symptomatic response to an AAD when the same AAD was continued for at least three months. Discontinuation of an AAD within three months because of recurrent symptomatic AF necessitating change in therapy was considered nonresponse. Additionally, a parallel animal study was conducted with 10 mice with diet-induced obesity (DIO) and 10 control mice. Inducibility of AF via rapid transesophageal pacing, as well as suppression of inducibility with either flecainide (class I AAD) or sotalol (class III AAD), were determined.
In the observational cohort, the mean age was 65 years; 39% were women, and 54% were obese. Symptomatic nonresponse to class I AAD occurred more frequently in obese patients than in nonobese patients (30% vs. 6%; P = 0.001). Most obese nonresponders were switched to a class III AAD, and several underwent ablation. In contrast, nonresponse rates to class III AADs was similar in both groups (9% vs. 5%), and most of those patients were either switched to amiodarone therapy or underwent ablation. In a multivariate analysis, obesity remained a significant factor associated with nonresponse to class I agents vs. class III agents. The odds ratio (OR) of nonresponse was 4.5 in obese patients (95% confidence interval [Cl], 1.84-11.2) vs. 1.34 in nonobese patients (95% CI, 0.28-6.36). Female sex also was associated with a higher likelihood of nonresponse to AADs (OR, 2.3; 95% CI, 1.07-4.99), as was hyperthyroidism (OR, 4.95; 95% CI, 1.23-20).
In mice, pacing-induced AF was achieved in 100% of DIO mice vs. 30% of nonobese mice (P < 0.001). The DIO mice showed a greater reduction in AF burden when treated with the class III agent sotalol vs. the class I agent flecainide (85% vs. 25%; P < 0.01). The authors concluded the human and mice data supported the hypothesis that obesity differentially mediates response to AAD in subjects with AF, with a relative reduction in the effectiveness of sodium channel blockers (class I AAD).
The study adds additional valuable data to our growing body of knowledge about the effects of obesity and AF. Previous clinical trials have demonstrated slowing and even reversal of AF progression with weight-loss management and aggressive risk factor modification (REVERSE-AF, discussed in the April 2019 issue, available at this link: http://bit.ly/2uskkmO), as well as reduced incidence of AF in obese patients who undergo bariatric surgery (discussed in the March 2017 issue, available at this link: http://bit.ly/39jCvKx). It now appears obesity also may be associated with reduced efficacy of sodium channel blockers (or even proarrhythmia); Ornelas-Loredo et al hypothesized this to be related to obesity-mediated modulation of the cardiac sodium channel.
If additional prospective data confirms this, these findings carry important implications for medical management of AF. The sodium channel blocking agents, specifically class Ic medications, such as flecainide and propafenone, often are first-line AADs for rhythm control in patients with AF. They have the advantage of safe outpatient initiation and a generally well-tolerated side effect profile. In contrast, class III drugs often require inpatient hospitalization for initiation, more drug-drug interactions, and arguably more proarrhythmia. However, they were effective for at least six months in 14 of 19 obese patients who failed class I therapy and were switched to them. If nearly one-third of obese patients will experience symptomatic AF recurrence within three months of maximum-tolerated class I doses, clinicians may wish to consider modifying their initial drug therapy discussions to favor a class III agent.
That said, there were multiple limitations to this study, many of which the authors described well. Principally, significant effects of confounding cannot be ruled out despite extensive efforts to account for them statistically. The reasoning for why some patients in the observational cohort were initially treated with class I agents and others with class III agents initially are not explored, and other comorbidities found commonly in obese patients (and that might affect medication response) still may play a role.
Furthermore, while obesity as a dichotomous variable (with BMI cutoff at 30 kg/m2) proved a significant risk factor for nonresponse to class I drugs, BMI as a continuous variable was not. In the mouse cohort, the authors never specifically discussed the response to sotalol vs. flecainide in the few control mice with inducible AF. Thus, it is difficult to prove whether the differential response seen in DIO mice is an effect of obesity or simply a characteristic of these mice.
For now, I would suggest these findings be applied in two principal ways. First, maintain a lower threshold to use a class III AAD as first-line drug therapy or transition to one sooner in obese patients with AF. Second, continue to encourage weight loss and risk factor modification above all in the management of AF in obesity.
In an observational cohort of patients with atrial fibrillation, obese patients were less likely than nonobese patients to avoid symptomatic recurrence on sodium channel blocking agents in contrast to a roughly equivalent response in both groups to potassium channel blocking agents.
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