Quality of life endpoints are sufficient for approving implantable pacemakers and defibrillators as treatments for atrial fibrillation, even without assurances that the devices provide long-term clinical benefit, FDA's Circulatory Systems Device Panel concluded April 6 in Gaithersburg, Maryland.

"With modern approaches to anticoagulation, trying to show a difference in embolic events would not be a reasonable undertaking," Michael Domanski, MD, National Institutes of Health, explained. "One can certainly use quality of life as something you can randomize and ascertain an endpoint. It is a little bit softer endpoint, but in the end it is what we [base] many of our decisions in atrial fibrillation on...when we do it clinically."

Speaking on behalf of Medtronic, Michael Gold, MD, University of Maryland, agreed with the panel that choosing a reduction in embolic events as a clinical endpoint was not appropriate.

"I am unaware of any data to suggest that any treatment to prevent atrial fibrillation prevents embolic complications," Gold maintained. "So I would not at this point tie any therapy or efficacy to a necessary reduction of embolic events."

Mortality also is problematic as a clinical endpoint, panel members agreed. Given the relatively low incidence of death, powering a study to test for it would require an unusually large number of patients.

Currently, physicians take two approaches in pacing for atrial fibrillation. Gold descibed them as "early," or painless, and "late," or shock treatment.

In addition to quality of life endpoints, the panel seemed comfortable with using a 25-35% reduction in atrial fibrillation burden or duration for pacing treatments, and a 70% atrial fibrillation termination in shock treatments as endpoints.

The panel also was convened to review study designs for catheter-based pulmonary vein ablation techniques for curing atrial fibrillation. Two modalities currently are used by clinicians - PV ablation and linear MACE ablation.

However, study design for the latter method already was addressed by the panel at a July 1998 meeting (¹ Also see "Non-Randomized Trials Okay For Atrial Fibrillation RF Ablation Trials - Panel" - Medtech Insight, 3 August, 1998.).

PV ablation, developed since the July 1998 meeting, presents a different set of issues with respect to trial design.

The technique requires the electrophysiologist to pinpoint the location of the fibrillation. Unfortunately, many patients do not have constant symptoms, which can make it difficult to determine where ablation is necessary if the patient is not experiencing atrial fibrillation in the operating room.

Panel members recommended that subjects enrolled in clinical studies have frequent premature atrial contractions (PAC's) or more constant "little short runs of AFib."

The panel also pointed out that patients should not have major structural heart disease.

The panel's discussion may also have brought to light a novel method of locating foci. Speaking during an open portion of the meeting, Warren Jackson, MD, University of Oklahoma, discussed a technique under evaluation in his lab that would help identify the pulmonary veins responsible for atrial fibrillation while a patient was not experiencing symptoms.

"A lot of the information that is coming out indicate that the largest pulmonary veins are likely to be the trigger," Warren informed the panel. Data coming out of the University of Oklahoma "suggest that if you look at the two largest pulmonary veins, the triggers for AFib will be found in 84% of patients within the two largest pulmonary veins."

Such a parameter would open up a larger patient population for ablation treatment. "It is a major goal to be able to avoid the need to identify which is the culprit vein," Jackson said. "That is technically very difficult."

While unaware of the approach before the meeting, both FDA and panel members appeared excited by Jackson's report. "I think that we would be interested in seeing the data supporting this position," FDA staffer Jim Dillard remarked.

For PV ablation studies in general, the panel concluded that single-arm, prospective baseline studies were likely the most appropriate. This decision mirrors the opinion given at the 1998 ablation meeting.

Pacemaker, Ablation Atrial Fibrillation Studies Evaluated By FDA Panel

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