Risks associated with Medtronic’s Phased RF catheter ablation system for atrial fibrillation outweigh the benefits of the device, FDA’s Circulatory System Devices panel concluded in an 8-2 vote on Oct. 27.

Key safety risks cited by the panel, including a 2.8% stroke rate observed among pivotal study patients at one month, led the advisory group to vote 9-1 that the data submitted in support of Medtronic’s PMA do not support device safety.

On the plus side, with 10 votes, the device did receive unanimous agreement that it was effective.

“I have ongoing concerns” about safety, “specifically the stroke risk,” said panel member Richard Page, in expressing the view of a majority on the panel.

“I recognize these are risky procedures, but the risk seems to be beyond what I would have expected,” said Page, who is a professor of medicine at the University of Wisconsin.

“It is the feeling of the panel that this system is effective, but there are concerns that the safety bars have not been met,” summarized panel chair Clyde Yancy, professor at Northwestern University’s Feinberg School of Medicine in Chicago.

The incidence of peri-procedural stroke commonly reported in the catheter AF ablation literature ranges from 0% to 1.7%, FDA noted in PMA review materials released Oct. 25.

The panel had a difficult time teasing out the exact cause of the high peri-procedural stroke rate. “How much of this is due to the anti-coagulation approaches that were taken, how much is due to operator inexperience and how much is due to the device itself is hard to say,” said panel member David Good, a neurologist at the Pennsylvania State Milton S. Hershey Medical Center.

The Phased RF ablation system uses radiofrequency energy to treat persistent or long-standing persistent atrial fibrillation. The system consists primarily of a multichannel radiofrequency ablation generator and related cardiac ablation catheters.

The firm announced Oct. 10 that it had met its effectiveness endpoint, but failed to reach an anticipated safety endpoint for its 210-person randomized TTOP-AF trial supporting its June PMA submission. (See “ Also see "Medtronic Gears Up For FDA Panel With Mixed Results From AF Ablation Trial" - Medtech Insight, 17 October, 2011. ” – “The Gray Sheet” Oct. 17, 2011.)

The trial enrolled 138 patients who received catheter ablation treatment and 72 who received traditional medical treatment with antiarrhythmic drugs and direct-current cardioversion.

The acute safety event rate in the ablation arm was 12.3% with a 95% upper confidence interval of 19% – missing the pre-specified endpoint goal of 16%.

Among 176 patients who underwent at least one study procedure (43 control subjects eventually became crossover patients for ablation), five experienced a procedure- or device-related ischemic stroke within one month (2.8%).

By comparison, no strokes were observed in six months of follow-up among control subjects in the study.

Seven subjects (4%) who received ablation also experienced pulmonary vein stenosis or narrowing – an adverse event that panel members generally agreed was too high.

“I recognize these are risky procedures, but the risk seems to be beyond what I would have expected” – panel member Richard Page, University of Wisconsin

FDA also sought the panel’s input on the safety profile associated with a specific pulmonary vein ablation catheter used with the system, which was found in three recent peer-reviewed manuscripts to be associated with a 37.5%-41.6% incidence of asymptomatic cerebral embolic lesions.

The panel generally felt that the findings signaled additional safety concerns that should be included in FDA’s approval decision, but that it was not clear what was driving the increased lesion rate.

All told, 38 subjects who underwent at least one study procedure experienced 41 serious adverse events within six months. In addition to stroke and pulmonary vein stenosis, events included hypotension (three patients), transient ischemic attacks (two patients) and one death, which both Medtronic and FDA said was related to the procedure but not the device.

Prior to the panel votes and following heated deliberations on the safety issue, David M. Steinhaus, VP and medical director of cardiac rhythm disease management for Medtronic, urged the panel to view the device as a first-of-its-kind approach to treating persistent AF – a more severe, longer-lasting form of atrial fibrillation than paroxysmal AF.

The two catheter ablation devices currently FDA-approved for AF – Johnson & Johnson/Biosense Webster’s ThermoCool radiofrequency system and Medtronic’s Arctic Front cryo-balloon system – are approved for paroxysmal AF.

If approved, Medtronic’s Phased RF ablation system would be the first catheter ablation system available to treat persistent AF.

The firm “looks forward to continuing discussions with FDA to determine the best path forward,” said Reggie Groves, VP and general manager of Medtronic’s AF Solutions unit, following the hearing.

Medtronic acquired the Phased RF technology through its purchase of Ablation Frontiers in 2009.

Effectiveness Solid; Gender Analysis Iffy

Despite the divisions over safety, the advisory group generally praised the efficacy data during its review.

In the TTOP-AF trial, researchers found that 55.8% of ablation patients experienced a reduction in AF and atrial flutter burden of greater than 90%, and did not need antiarrhythmic drug therapy at six months, versus 26.4% in the traditional therapy group who met these primary effectiveness endpoint thresholds.

During the hearing, FDA posed questions to the panel related to different ablation success criteria from the Heart Rhythm Society, which, if applied, would have resulted in only 37% of subjects in the ablation arm being classified as successes. But the panel concluded that the sponsor’s analysis was fine as is.

One efficacy issue that did pose a concern for panel members, however, was the fact that 83% of the enrolled study subjects were males.

“The bottom line is the efficacy results are driven by men,” said panel member Scott Evans, senior research scientist in the department of biostatistics at Harvard’s School of Public Health. As for effectiveness in women, “we don’t have sufficient data to tell yet.”

Moreover, speaking anecdotally on their experience with higher complications typically seen in women in other catheter ablation procedures, panelists also expressed fears that a study population more evenly balanced by gender might have driven the adverse event rate higher.

The existing data on safety “could be the best-case scenario,” suggested Page.

FDA is working on guidance addressing strategies to encourage more women to participate in clinical device trials. (See “ Also see "Regulatory News In Brief" - Medtech Insight, 3 October, 2011. ” – “The Gray Sheet” Oct. 3, 2011.)

Post-Approval Study And Training

Medtronic has proposed a non-randomized post-approval study to monitor long-term effectiveness, acute and chronic safety, following 400 subjects for 36 months.

Hand in hand with that, Medtronic’s Steinhaus said during the panel meeting that the firm would also focus on incorporating lessons learned from the pivotal trial and the Heart Rhythm Society’s ablation guidelines into its physician training and education efforts going forward, due to the novelty of the procedure.

Panel members agreed that a rigorous and standardized training program for operators would be a key part of lowering adverse events.

“If this is to be approved and expanded, then we’re looking at an enormous morbidity burden of a learning curve,” said panel member Robert Jaquiss, a pediatric cardiac surgeon at the Duke University Medical Center.

“The technology is only as good as the person” using it, he added.

Some panelists also suggested that catheter design changes could address the incidence of asymptomatic cerebral embolic lesions, and that using a 3-D mapping system could give clinicians better visualization for the ablation procedure.

On Oct. 26, the FDA panel also reviewed AtriCure’s Synergy surgical ablation system for AF. (See “ Also see "FDA Panel Narrowly Endorses AtriCure’s Synergy For A-Fib Ablation" - Medtech Insight, 31 October, 2011. .”)

By Zach Miners

Safety Concerns Sink Medtronic A-Fib Catheter Ablation System At Panel

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