Atrial arrhythmia burden as an endpoint in clinical trials: is it the best surrogate? Lessons from a multicenter defibrillator trial.

Abstract

Therapies to treat atrial tachyarrhythmias need to be evaluated in controlled, randomized clinical trials in order to optimize patient outcomes. If the maintenance of sinus rhythm is the ultimate goal, then atrial tachyarrhythmia burden may serve as a useful endpoint. Atrial tachyarrhythmia burden is defined as the total duration of all atrial tachyarrhythmias divided by the follow-up time and includes asymptomatic as well as symptomatic episodes. The measurement of atrial tachyarrhythmia burden is more practical now than in the past because of the availability of implantable devices capable of monitoring atrial tachyarrhythmia episodes. The advantage of burden over other endpoints is that it is not subject to investigator bias and it does not have the sampling error associated with episodic rhythm monitoring or the monitoring of patient symptoms. The use of burden as a surrogate endpoint for clinical outcome facilitates the demonstration of a biological effect of a therapy on the triggers or substrates responsible for the arrhythmia. Therapies that reduce burden can then be further studied to assess more traditional endpoints. A recent multicenter trial examined the effect of device-based atrial therapies on burden in patients receiving an implantable cardioverter defibrillator (Medtronic 7250 Jewel AF) to treat ventricular tachyarrhythmias. Patients were randomized to 3-month periods of atrial therapies "ON" or "OFF" and subsequently crossed over. The atrial therapies resulted in a reduction of atrial tachyarrhythmia burden from a mean of 58.5 hours/month to 7.8 hours/month (P = 0.007). Based on the evidence of a biological effect of the atrial therapies (burden reduction) studies to determine of the effects of AT/AF prevention and termination algorithms on morbidity and quality of life in ICD recipients are underway.