Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia.1 The prevalence of AF in the general population increase with age, and is estimated to affect over 4% of the population above the age of 60 years.234 Foremost, electrical and chemical cardioversions have been successfully utilized for rhythm control in AF.5 However, it has been reported that cardioversion in patients with AF is associated with complications including thromboembolic events (5-7%) and bradyarrhythmias (0.8-1.5%).678 Adequate anticoagulation may, in part, attenuate the risk associated with thromboembolic events; in patients with adequate anticoagulation, the event rate is reported to be between 0.7% and 0.8%.9101112

Current guidelines advocate for patients with AF lasting more than 48 hours to achieve therapeutic International Normalized Ratio (INR) for 3 weeks prior to cardioversion and maintain anticoagulation treatment for at least 4 weeks following cardioversion. If patient has not been anticoagulated for the preceding 3 weeks, it is reasonable to perform a transesophageal echocardiography (TEE) prior to cardioversion.113 However, given these recommendations generally stem from small observational studies, therefore, there is a need for additional verification via larger sized datasets of varying study samples. Furthermore, in terms of bradyarrhythmia, the paucity of data regarding the predictors of cardioversion complications remains equivocal to date.141516 Hence, the comprehensive safety analysis including thromboembolic, bleeding, and arrhythmic events from electric cardioversion in recurrent and persistent AF in various ethnicities requires further clarification. In the current study, we explored the presence of risk factors and their association with thromboembolic, major bleeding, and arrhythmic events following electrical cardioversion of AF lasting beyond 48 hours with appropriate anticoagulation following current guidelines.

The present study comprised a retrospective analysis of 1100 patients from January 2005 through August 2013 at four tertiary hospitals in Korea. Although the number of cardioversion was 1597, this study evaluated only the initial cardioversion in each patient. Patients with AF with the duration of 48 hours or more taking warfarin and underwent electric cardioversion were enrolled for evaluation. Patients taking new oral anticoagulant were excluded. All case records were reviewed following the standardized data collection protocol for the purpose of obtaining information: baseline characteristics including age, gender, diabetes, hypertension, heart failure, and history of stroke or myocardial infarction; medication use; management of patients during the initial cardioversion and the 30-day follow-up period after cardioversion. The CHADS₂ score [Congestive heart failure, Hypertension, Age ≥75, Diabetes, prior ischemic Stroke, transient ischemic attack (TIA) or thromboembolism (doubled)], CHA₂DS₂-VASc score [Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 (doubled), Diabetes, prior ischemic Stroke, TIA or thromboembolism (doubled), Vascular disease, Age 65-74, gender category (female)], and HAS-BLED (Hypertension, Abnormal renal or liver function, Stroke, Bleeding tendency or predisposition, Labile INRs, Elderly, Drugs or alcohol abuse) were calculated as indices of thromboembolic or major bleeding risks. Before patients begin taking warfarin, INR was checked and warfarin was prescribed considering patient's body weight, age, and laboratory test result. Then, the dose was modulated according to the target INR level between 2.0 and 3.0 at 1 or 2 weeks interval. When INR level remained same for at least 1 to 2 weeks, INR level was measured once a month.

Diagnosis of AF was based on a 12-lead electrocardiogram (ECG) characterized by the absence of discrete P waves and an irregular ventricular rate. For the majority of patients, a single ECG was sufficient to secure diagnosis, assuming the patient is in AF at the time of the ECG. For the remaining patients, AF was diagnosed by employing a heart rhythm recording such as telemetry strip or Holter monitor. Synchronized direct-current cardioversions were performed according to the current guidelines with the monitoring of ECG, pulse rate, oxygen saturation, and cardiac telemetry under sedation with intravenous injection of pentothal sodium. Cardioversion energy was set to 100 to 200 joules for biphasic devices. Cardioversion was defined as successful if sinus rhythm was obtained and patient was discharged from the cardioversion unit in sinus rhythm. If first cardioversion had failed, second or third cardioversion was performed. To reduce the risk of thromboembolism following cardioversion, anticoagulation was performed according to current guidelines three to four weeks before and after cardioversion. Alternatively, TEE was performed to evaluate the presence of existing intra-cardiac thrombus within 24 hours before electrical cardioversion depending on the physician's decision. In some patients with lower INR levels, intravenous unfractionated heparin was administered at the time of cardioversion.

The outcome in this study was hospitalization due to cardiovascular events after cardioversion during 30 days, which comprised the following: 1) thromboembolic (stroke/TIA, systemic embolism), 2) major bleedings, and 3) arrhythmic events. Stroke was defined as the sudden onset of a focal neurological deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic, or unspecified. Hemorrhagic transformation of ischemic stroke was not considered hemorrhagic stroke. Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage. Systemic embolism was defined as an acute vascular occlusion of an extremity or organ documented by means of imaging, surgery, or autopsy. Major bleeding was defined as a reduction in the hemoglobin level of at least 20 g/L, transfusion of at least 2 unit blood, or symptomatic bleeding in a critical area or organ. Patients with symptomatic significant bradycardia were hospitalized. Significant bradycardia was defined as bradycardia requiring medication or pacing, heart rate lower than 40 beats per minute, or asystole lasting longer than 5 seconds. Other arrhythmic events including ventricular tachycardia and fibrillation also evaluated.

Continuous variables are reported as mean±standard deviation, and were analyzed using independent t-test. Categorical variables were reported as counts and proportions, and analyzed using Pearson's chi-square tests or Fisher's exact test, as appropriate. We performed univariate analysis and, with variables found to be statistically significant on univariate analysis, multivariate logistic regression analysis was performed to evaluate independent predictors for cardiovascular events. The SPSS statistical package (SPSS Inc., Chicago, IL, USA) was used to perform all statistical evaluations. A p value of <0.05 was considered statistically significant. The study protocol was approved by the Institutional Review Boards. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agreed to the manuscript as written.

The clinical characteristics of patients according to the thromboembolic or bleeding events are presented in Table 1. The average duration of anticoagulation before cardioversion was 96±52 days. Mean INR were 2.43±0.89 and 2.38±0.92 at the time of cardioversion and 30-day follow-up, respectively. The proportion of patients with INR ≥2 at the time of cardioversion were 89% (n=893). The antiarrhythmic drugs used at the time of cardioversion were flecainide (n=494, 45%), amiodarone (n=445, 40%), beta-blocker (n=585, 53%), calcium-channel blocker (n=226, 21%) and others (n=119, 11%). Cardioversion was successful in 947 patients (87%). In 1080 (98%) patients, follow-up more than 30 days were possible.