Transesophageal Echocardiography To Assess Embolic Risk in Patients with Atrial Fibrillation

Transesophageal echocardiography visualizes the left atrium and its appendage and is more sensitive than transthoracic echocardiography for diagnosing thrombi of the left atrium and the left atrial appendage and spontaneous echocardiographic contrast of the left atrium [1-3]. The left atrium and especially the left atrial appendage are the presumed sites of thrombus formation and sources of arterial emboli in patients with atrial fibrillation [4]. Patients with atrial fibrillation and a history of stroke or embolism were shown to have a higher prevalence of thrombi of the left atrium or the left atrial appendage, a higher prevalence of spontaneous echocardiographic contrast, and a larger left atrial appendage than patients with no history of stroke or embolism [2, 5, 6]. However, whether these abnormalities are predictors for stroke or embolism remains controversial [7, 8]. Furthermore, no studies have determined whether transesophageal echocardiography helps to assess risk for stroke or embolism in outpatients with atrial fibrillation who have no history of stroke or embolism or whether transesophageal echocardiography is useful in the decision to initiate anticoagulation. We therefore performed a prospective, multicenter study of outpatients with atrial fibrillation who had not recently had stroke. We sought to determine whether thrombi of the left atrium or the left atrial appendage, spontaneous echocardiographic contrast, and size of the left atrial appendage are associated with stroke or embolism. Our hypothesis was that patients with thrombi of the left atrium or the left atrial appendage, spontaneous echocardiographic contrast, and enlargement of the left atrial appendage have a higher rate of stroke or embolism than do patients without these abnormalities. The baseline clinical and echocardiographic characteristics of our study sample have been reported elsewhere [9]. Methods Patient Recruitment Our study was conducted in Austria and Slovakia. At the beginning of the study, general practitioners and internists from surrounding participating centers were informed about the study and were asked to refer patients who had constant or intermittent atrial fibrillation. At each patient's first visit, a cardiologist recorded baseline data, associated illnesses, clinical characteristics (definitions of which are listed in Appendix 2), and the cause of atrial fibrillation. A 12-lead electrocardiogram was recorded on 2 separate days. We excluded patients with prosthetic valves and those who were already receiving anticoagulation. Current therapy with aspirin was not an exclusion criterion. Patients who had mitral valve stenosis or had recently had stroke were excluded because anticoagulation was indicated for such conditions. For the definition of recent stroke, we chose a cutoff value of 1 year because a previous study reported that the risk for recurrent stroke was increased in patients who had had an ischemic event in the previous year [10]. Echocardiography For transthoracic echocardiography, 2.5- or 3.5-MHz probes were used. For M-mode measurements, we applied the recommendations of the American Society of Echocardiography [11]. M-mode measurements were performed on-line and were documented on printouts. Regional wall-motion and valvular abnormalities were recorded. In patients without regional wall-motion abnormalities, left ventricular systolic function was assessed by calculation of left ventricular fractional shortening. For transesophageal echocardiography, biplane 5-MHz probes were used in 64% of the patients and monoplane 5-MHz probes were used in 36%. After local anesthesia with lidocaine spray was administered, the probe was introduced into the nonsedated patients, who lay on their left side. The entire study was recorded on S-VHS videotapes. The cardiac chambers and valves were investigated by using all obtainable views [12, 13]. Special care was taken to visualize the whole cavity of the left atrium and its appendage from different planes, with the tip of the probe slightly flexed. The size of the left atrial appendage was measured off-line. A frame that best visualized the left atrial appendage with respect to its orifice, extension, and delineation of borders was selected just before the QRS complex. The length of the left atrial appendage was defined as the distance between the limbus of the left superior pulmonary vein and the apex of the left atrial appendage; the width of the left atrial appendage was defined as the longest distance between the lateral and ventricular left atrial appendage wall, measured in a line perpendicular to the course of the left atrial appendage curvature; and the left atrial appendage area was defined as described elsewhere [14]. For the assessment of intra- and interobserver deviations, left atrial appendage size was measured 1 year after the initial measurement in 20 randomly selected video recordings by the same observer and in 60 randomly selected video recordings by three observers from different centers. A thrombus of the left atrium or left atrial appendage was considered definite if at least three of the following five criteria were present: clear borders, echogenicity different from that of surrounding structures, independent mobility, longest diameter greater than 15 mm, and evidence of thrombus in more than one imaging plane [15]. A second observer from a different center reviewed video recordings to confirm diagnosis of thrombus of the left atrium or left atrial appendage. A thrombus was considered probable if only two criteria were present or if the observers disagreed. Spontaneous echocardiographic contrast was diagnosed in the presence of dynamic smoke-like echoes within the left atrium or left atrial appendage with a characteristic swirling motion that was distinct from white noise artifact [16]. When spontaneous echocardiographic contrast was suspected, the gain settings were decreased in a stepwise manner to exclude artifact caused by excessive gain. The compression and gain controls were then adjusted to ensure the best possible visualization. Spontaneous echocardiographic contrast was not quantified. A second observer from a different center checked the diagnosis of spontaneous echocardiographic contrast by reviewing all video recordings. When the observers disagreed about the presence or absence of spontaneous echocardiographic contrast, the decision made at the time of examination was chosen. This was done because spontaneous echocardiographic contrast was not always visible on review of the video recordings. Outcome Events Primary events were stroke and embolism that extended to viscera or extremities. Stroke was defined as acute onset of a focal neurologic deficit that lasted more than 24 hours and was consistent with a vascular event. Severity and subtypes of stroke were assessed according to established criteria [17]. Embolism extending to viscera or extremities was defined as a sudden onset of pain that was associated with typical findings on Doppler ultrasonography, angiography, surgery, or autopsy. Secondary events were the need for anticoagulation during follow-up in patients who were primarily receiving aspirin and death not caused by stroke or embolism. Death not caused by stroke or embolism was classified as cardiac or noncardiac on the basis of information from the treating physician and the patient's family. Follow-up Visits took place 3, 6, 12, 18, and 24 months after study entry. After a follow-up period of at least 2 years (ending in February 1994), it was evident that the number of primary outcome events was low. We therefore prolonged the follow-up period and planned further visits, one to be held in 1994 and one to be held in 1995. Patients who were unwilling or unable to attend the visits were contacted by telephone. Medical records were obtained for patients who had been admitted to a hospital. If a patient had died, an autopsy report or death certificate was obtained. Treatment and Ethical Considerations Although our study was designed to be observational, we recommended antithrombotic treatment to the patients because of ethical considerations. Because patients with thrombi of the left atrium or left atrial appendage are considered to have a high risk for embolism, we recommended that they receive anticoagulation. The target range for the international normalized ratio was 2.0 to 3.0, and the treating physicians monitored the ratio [5, 18]. We recommended that the remaining patients receive aspirin, 160 mg/d, because preliminary data indicated that aspirin reduces the risk for stroke or embolism in patients with atrial fibrillation [19]. The institutional review board of the participating centers approved the study. Patients were informed about the background and the procedures of the trial, and informed consent was obtained according to the rules of each center. Statistical Analysis For baseline data, group comparisons were done by analysis of variance for normally distributed data and by the nonparametric Kruskal-Wallis test for data that were not normally distributed. If appropriate, we used the Scheffe post hoc test. The Wilk-Shapiro test was used to check for normality. Contingency table methods, including the chi-square test and the Fisher exact test, were used to analyze categorical data. We used the Cox proportional-hazards model to obtain estimates of relative risk and 95% CIs for all univariate and multivariate analyses of time-to-event data. All tests were two-sided. The level of significance assumed was an level of 0.05. We used SAS software (SAS Institute, Cary, North Carolina) for analyses. Role of Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data; did not review the manuscript at any time; and were not involved in submitting the paper for publication. Results Patients Patients were recruited between January 1990 and February 1992. Of the 474 consecut