Stroke Risk in Atrial Fibrillation

Abstract & Commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco does research for Medtronic, is a consultant for Medtronic, Novartis, and St. Jude, and is a speaker for Boston Scientific.

Source: Healey JS, et al, for the ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120-129.

The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) tested two hypotheses. The first was to see if subclinical episodes of high atrial rates detected by implanted devices are associated with an increased risk for stroke in patients without clinically manifest atrial fibrillation (AF). The second was to evaluate the efficacy of atrial overdrive pacing algorithms for preventing the development of clinical AF. Patients were eligible for inclusion in the study if they were 65 years of age or older with a history of hypertension and had undergone implantation of a St. Jude Medical dual-chamber pacemaker or implantable cardioverter-defibrillators (ICDs) in the preceding 8 weeks. Patients with a history of documented AF or atrial flutter and those who required treatment with a vitamin K antagonist for any reason were excluded. At the initial study visit, the pacemaker's device was programmed so an atrial high rate episode was detected when the atrial rate reached 190 beats per minute. Three months later, devices were interrogated to classify patients according to whether a subclinical atrial tachycardia had occurred since the time of enrollment. A subclinical atrial tachycardia was defined as an episode of a rapid atrial rate lasting more than 6 minutes as detected by the pacemaker or the defibrillator. At that 3-month visit, patients with pacemakers (but not patients with ICDs) were randomly assigned to have either a continuous atrial overdrive pacing function programmed to either "on" or "off." This algorithm would pace the rate at a slightly higher rate than the patient's intrinsic sinus rate in hopes of preventing AF. After this visit, patients were followed every 6 months until the end of the study. For the portion of the study evaluating the prognostic value of subclinical AF, the primary outcomes were ischemic stroke and systemic embolism. The primary outcome of the trial of overdrive pacing was the occurrence of symptomatic or asymptomatic atrial tachyarrhythmia lasting more than 6 minutes.

Over a 5-year period, the study enrolled 2451 pacemaker patients and 129 ICD patients. During the first 3 months after implant, at least one atrial tachyarrhythmia was detected in 261 patients (10.1%). During the same period, a clinically evident atrial tachyarrhythmia occurred in seven patients. Among patients with a subclinical atrial tachyarrhythmia, the median number of episodes was two. Over a mean of 2.5 years of subsequent follow-up, subclinical atrial tachyarrhythmias occurred in an additional 633 patients (24.5%). Clinical atrial tachyarrhythmias documented by surface electrocardiograms occurred in 41 of the 261 patients (15.7%) who had a subclinical atrial tachyarrhythmia during the initial 3-month observation period and in 71 of the 2319 (3.1%) patients who had not had an atrial tachyarrhythmia during that time. During follow-up, 11 of the 261 patients (4.2%) in whom a subclinical atrial tachyarrhythmia had been detected experienced an ischemic stroke or systemic embolism for an annual rate of 1.69%. In comparison, 40 of 2319 patients (1.7%, 0.69% per year) without a subclinical atrial tachyarrhythmia at the 3-month time point experienced a stroke or systemic embolism. A time-dependent analysis, including all episodes of atrial tachyarrhythmias during follow-up, showed that detection of episodes lasting longer than 6 minutes as compared to detection of no episodes was associated with an increased risk of ischemic stroke or embolism with a hazard ratio of 1.76. When the patients with episodes of device-detected atrial tachyarrhythmia were stratified into quartiles based on the duration of the longest episode, there was an increase in risk in the group with the longest episodes (> 17.72 hours). The number of episodes of subclinical atrial tachyarrhythmias did not show a significant relationship to event rates. No estimate of overall AF burden was presented. The relative risk of ischemic stroke or systemic embolism was also related to baseline risk of stroke as assessed by the CHADS2 score. In patients with a CHADS2 score of > 2 and a subclinical atrial tachyarrhythmia, the event rate was 3.78% per year for those with 6-minute high atrial rate episodes compared to 0.97% per year for those without. The portion of the study that assessed atrial overdrive pacing showed that there was no decrease in AF (annual rate 1.96 on vs 1.44 off) or in thromboembolic events (0.78 on vs 0.86 off).

The authors conclude that subclinical atrial tachyarrhythmias are frequent in patients with pacemakers and a history of hypertension, but no prior diagnosis of clinical AF. The detection of subclinical atrial tachyarrhythmias of at least 6 minutes duration is associated with an increased future risk of stroke.

Commentary

Based on the results of large trials on anticoagulation in patients with AF, current guidelines recommend long-term oral anticoagulation for high-risk patients with both persistent and paroxysmal clinically manifest AF. However, asymptomatic, self-terminating episodes of atrial tachyarrhythmias are frequently seen when patients undergo prolonged ECG monitoring or during interrogation of pacemakers or ICDs. Do all these patients need chronic anticoagulation? The ASSERT data would suggest that at least those patients in the quartile with longer episodes (> 17.72 hours) and a CHADS2 score ≥ 2 should be anticoagulated.

The ASSERT authors chose to base their analysis on atrial high-rate episodes of at least 6 minutes duration. However, in comparison to shorter episodes, 6-minute episodes are relatively uncommon. Many patients with pacemakers or ICDs will have more shorter atrial high-rate episodes detected when their devices are interrogated. In some, even though each episode is short, the overall AF burden may be substantial. We still need further definition of the lower boundary that should trigger a decision to anticoagulate.