Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 ± 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for ≥6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 ± 25 vs 22 ± 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA.
The presence of obstructive sleep apnea (OSA) has been demonstrated to decrease the efficacy of several therapies for atrial fibrillation (AF). In a study of patients who underwent electrical cardioversion, the risk for AF recurrence was increased in those with OSA compared to unaffected subjects, although nearly 50% of the OSA group was treated with antiarrhythmic drugs (AAD) compared to <20% of the non-OSA group. In addition, when severe OSA is present, an increased rate of AF recurrence after catheter ablation has been consistently reported. The impact of OSA on the efficacy of AAD therapy for AF has not been robustly explored. Given that pharmacologic management of AF is common and is used before and after electrical cardioversion and catheter ablation, characterizing the impact of OSA on AAD therapy for AF is clinically important. In this study, we tested the hypothesis that treatment of AF-related symptoms with AADs is less successful in patients with severe OSA than in those with milder forms of the disease.
Methods
The cohort used for this study and the techniques for measuring AF symptom burden have been previously described. Briefly, adults with documented AF or atrial flutter treated with ≥1 conventional AAD were prospectively enrolled in the Vanderbilt AF Registry, a clinical and genetic database. At enrollment and at 3, 6, and 12 months of follow-up, patients completed the modified University of Toronto AF Severity Scale (range 3 to 30) to gauge symptomatic AF burden. The AADs reported here reflect the agents that patients were on at the time of their enrollment in the Vanderbilt AF Registry.
Arterial hypertension was defined by a history of hypertension and/or the presence of antihypertensive therapy. Criteria for coronary artery disease included a history of myocardial infarction or typical angina, previous coronary bypass surgery or angioplasty, and drug treatment. Heart failure was defined by history and/or drug treatment for heart failure. Left atrial and left ventricular measurements from M-mode echocardiograms were made at the time enrollment if a recent echocardiogram (<3 months) was not available in the medical record. The echocardiograms were read by an experienced physician blinded to the genotype status of the patient. The echocardiograms were evaluated according to the recommendations of the American Society of Echocardiography.
Response to AAD therapy was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for ≥6 months after enrollment in the AF registry or demonstrated ≥75% reduction in symptomatic AF burden (on the basis of the composite score for the frequency, duration, and severity of symptoms). Nonresponse was defined as <75% reduction in symptomatic AF burden score and a change to another AAD or to nonpharmacologic therapy such as atrioventricular node ablation and pacemaker implantation.
The Vanderbilt AF Registry was screened for participants who underwent diagnostic overnight polysomnography for clinical reasons at the Vanderbilt Sleep Center. Sleep parameters were abstracted from clinical reports generated by specialists at our institution certified by the American Board of Sleep Medicine. If the study was a split-night examination, data from the diagnostic portion (without application of continuous or bilevel positive airway pressure) were used.
Full-night polysomnography was carried out using the Polysmith Sleep system (Nihon Kohden America, Inc., Foothill Ranch, California). Airflow was monitored by an oral-nasal sensor, and respiratory effort was monitored by impedance plethysmography. Electroencephalograms, electro-oculograms, and submental electromyograms were recorded according to American Academy of Sleep Medicine standards. A single lead electrocardiographic signal as well as oxyhemoglobin saturation via digital pulse oximetry were continuously recorded throughout the study. Apnea was defined as a ≥90% decrease in the airflow signal from baseline for ≥10 seconds. Hypopnea was defined as a ≥50% reduction in airflow from baseline for ≥10 seconds accompanied by a decrease in oxyhemoglobin saturation of ≥4%. Subjects with apnea-hypopnea indexes (AHIs; the sum of apnea and hypopnea episodes divided by the total sleep time) ≥5 events/hour were considered to have OSA. The severity of OSA was further categorized by AHI as follows: mild, 5 to 15 events/hour; moderate, 16 to 30 events/hour; and severe, >30 events/hour. The minimum oxygen saturation was taken as the nadir of the continuous oximetric reading during polysomnography.
Data are reported as mean ± SD for continuous variables and as percentages for categorical variables. Differences between groups were evaluated using Wilcoxon’s rank-sum test for continuous variables and Pearson’s chi-square test for categorical variables. Analyses were performed with the R software package version 2.12.0 (R Project for Statistical Computing, Vienna, Austria). Comparisons were considered statistically significant for p values <0.05 for 2-tailed tests.
Results
The analysis consisted of 61 subjects who underwent polysomnography and had serial evaluations of AF symptoms. Table 1 lists their demographics, cardiac histories, echocardiographic characteristics, and key sleep parameters stratified by response to AADs. Two-thirds were taking β blockers and/or calcium channel blockers; 50% were taking amiodarone, 25% were taking sotalol, and 25% were taking either flecainide or propafenone. Approximately half of the cohort (49%) had symptomatic response to AADs.
| Characteristic | Entire Cohort | Nonresponders | Responders |
|---|---|---|---|
| (n = 61) | (n = 31) | (n = 30) | |
| Age (years) | 64 ± 9 | 65 ± 8 | 64 ± 10 |
| Women | 34% | 35% | 33% |
| Caucasian | 89% | 77% | 100% |
| Body mass index (kg/m 2 ) | 34 ± 7 | 34 ± 8 | 34 ± 7 |
| Hypertension | 66% | 65% | 67% |
| Coronary artery disease | 31% | 25% | 38% |
| Heart failure | 20% | 22% | 17% |
| AF | |||
| Paroxysmal ⁎ | 61% | 50% | 72% |
| Persistent ⁎ | 26% | 39% | 14% |
| Permanent | 12% | 11% | 14% |
| Baseline AF burden score | 19 ± 8 | 20 ± 9 | 18 ± 8 |
| Echocardiographic parameters | |||
| Left atrial dimension (mm) | 46 ± 8 | 47 ± 7 | 45 ± 9 |
| Left ventricular ejection fraction (%) | 50 ± 11 | 49 ± 12 | 52 ± 11 |
| Left ventricular hypertrophy | 47% | 48% | 45% |
| Right ventricular systolic pressure (mm Hg) | 38 ± 12 | 38 ± 12 | 38 ± 11 |
| Polysomnographic parameters | |||
| AHI (events/hour) ⁎ | 28 ± 22 | 34 ± 25 | 22 ± 18 |
| Minimum oxygen saturation (%) | 81 ± 8 | 80 ± 8 | 82 ± 9 |
| Portion of total sleep time in rapid eye movement (%) | 13 ± 8 | 15 ± 9 | 12 ± 7 |
| Severe OSA ⁎ | 38% | 52% | 23% |
⁎ p ≤0.05 for comparison between nonresponders and responders.
Among the non-sleep-related variables, only the type of AF differed between the nonresponders and responders, with paroxysmal AF being more common and persistent AF less common in the responders. The AHI and the frequency of severe OSA were increased in nonresponders compared to responders. Subjects who did not respond to AADs had higher AHIs (34 ± 25 vs 22 ± 18 events/hour, p = 0.05) and more commonly had severe OSA (52% vs 23%, p <0.05) than responders. There was no difference in body mass index between responders and nonresponders, suggesting that obesity itself did not influence the response to AADs in this cohort.
Table 2 lists cohort characteristics on the basis of OSA severity. Fewer than 1/3 of those with severe OSA responded to AAD therapy, but the response rate was twice as high in those with nonsevere OSA (61 vs 30%, p = 0.02). There were modest differences in the distributions of paroxysmal, persistent, and permanent AF when stratified by OSA status that did not reach statistical significance. This finding suggests that the response to AADs was not confounded by a disproportionately high prevalence of “resistant” AF. The prevalence of hypertension and coronary artery disease, both implicated in the pathogenesis of AF, were higher in the severe OSA group compared to the nonsevere group, raising the possibility that the higher nonresponse rate observed in the severe OSA group was confounded by higher rates of these conditions. However, OSA is a known risk factor for hypertension and coronary disease. Therefore, the increased prevalence of these conditions in the severe OSA group is not entirely unexpected and could be partially attributable to the increased OSA burden.
