Watchman Wins Substantial Endorsement from FDA Advisory Panel
After more than 4 years, a US Food and Drug Administration (FDA) advisory panel gave almost unanimous support for approval of the Watchman left atrial appendage (LAA) occlusion device for use in patients with nonvalvular atrial fibrillation (A-fib).
The Circulatory System Devices Panel voted 13 to 1 in favor of the Watchman device (Boston Scientific, Natick, MA), a fabric-covered nitinol cage developed to prevent embolization of thrombi that form in the LAA. The vote was based on the panel believing there is a reasonable assurance of device safety and effectiveness and that the probable benefits of the device outweigh the probable risk.
A Long, Winding Road
The recommendation was based on results of the PREVAIL trial and additional long-term follow-up data from PROTECT AF. The latter, originally presented in March 2009 at the American College of Cardiology Annual Scientific Session/i2 Summit and published in the Lancet later the same year, randomized 707 patients with nonvalvular A-fib to percutaneous LAA closure with Watchman (n = 463) or ongoing warfarin treatment alone (n = 244). Although the device was found to be noninferior to warfarin in terms of preventing stroke, systemic embolism, and cardiovascular death, its use was accompanied by a higher risk of complications, mostly pericardial effusion and procedural stroke.
In April 2009, an FDA panel voted 7 to 5 in favor of the device, but with several stipulations. First, panel members said the device should be only approved in warfarin-eligible patients. Second, the panel advised that physicians undergo a training program before using the device and perform procedures only at facilities with cardiac surgery backup. Lastly, the panelists also requested that Atritech, the original manufacturer, conduct a registry study as well as continue follow-up through 5 years in PROTECT AF.
The resulting Continued Access Protocol (CAP) registry showed significantly better procedure times, implant success rates, and safety outcomes compared with those originally seen in PROTECT AF. Moreover, in PREVAIL the Watchman met 2 of 3 primary endpoints over warfarin therapy in a Bayesian analysis. However, PREVAIL and its investigators were not without controversy, especially after it was pulled from the 2013 American College of Cardiology Annual Scientific Session/i2 Summit program at the last minute only to be later released by Boston Scientific. Additionally, 4-year results from PROTECT AF, presented in May 2013, at the Heart Rhythm Society 34th Annual Scientific Sessions in Denver, CO, showed continued superiority of Watchman over warfarin with regard to stroke avoidance and mortality.
Lastly, the ASAP trial, published in the Journal of the American College of Cardiology in April 2013, demonstrated device safety in patients contraindicated to oral anticoagulation with 77% fewer strokes than expected given the population.
‘Creative Trial Methods’ Increased Support
FDA advisory panel member David E. Kandzari, MD, of Piedmont Heart Institute (Atlanta, GA), told TCTMD in an e-mail communication that “despite the uniformly positive voting, the dataset was challenging for the panel to interpret efficacy given that the methods were largely based on modeling estimates using Bayesian statistics with only 28% of the PREVAIL 18-month patient data available.”
Therefore, conclusions regarding efficacy were “based on interpretation of the totality of data with the Watchman device, which also included extended term follow-up from the initial PROTECT AF trial,” he said. “Although rates of ischemic stroke and systemic embolism were numerically higher with the Watchman device, the panel overall believed the event rates in the device and warfarin arms were clinically similar.”
Additionally, Dr. Kandzari noted the panel was “particularly reassured with improved procedural safety in both the CAP and PREVAIL studies, and that the measures implemented to improve procedural success had demonstrated a more than halving of early complications observed in PROTECT AF.”
Commenting on the regulatory process thus far, he said it “represented a positive, collaborative effort between FDA and industry to resolve outstanding dilemmas from the [PROTECT AF] trial with more creative trial methods that led to accelerated device approval.”
Diligence Pays Off
In a telephone interview with TCTMD, Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), said given the results of the advisory panel vote, he has every expectation that the FDA will approve the Watchman device; however, the timeline remains unknown. The agency is not required to follow the recommendations of its advisory panels, but it usually does.
The only “critical issue” will be for which patients the device will be indicated, Dr. Sommer added, since all of the Watchman trials, except ASAP, included only warfarin-eligible patients. “The population that really needs this is warfarin-ineligible patients,” he explained, adding that there is no appropriate, controlled method of studying the device in this patient group.
“Once they approve this, all of those [warfarin-ineligible] patients will likely end up getting treated off-label” anyway, he said. “We know that warfarin is better than aspirin, so the bottom line is we know that [Watchman is] going to be used in [warfarin-ineligible patients] whether it’s approved or not.” Still, the FDA’s opinion will likely be linked with what the Centers for Medicare and Medicaid Services agrees to approve, he continued.
Overall, Dr. Kandzari likened the regulatory process for Watchman to that of the Sapien TAVR device (Edwards Lifesciences, Irvine, CA) “where it was a really well done study, there’s really solid data, and that helps the FDA enormously to make a decision. . . . It’s a very good lesson for anyone else trying to get approval for a device about how diligent you have to be.”
US Food and Drug Administration. Boston Scientific Watchman left atrial appendage closure therapy [executive summary]. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/
Accessed December 12, 2013.
- Dr. Kandzari reports receiving research and grant support from Abbott, Boston Scientific, and Medtronic and serving as a consultant for Boston Scientific and Medtronic.
- Dr. Sommer reports serving as a PI for both the PREVAIL trial and the CAP2 registry.