Time May Be Running Out for Watchman Amid Weak Support From FDA Panel
The third time was not the charm for Watchman. After a full day of reviewing the totality of data for the left atrial appendage (LAA) occlusion device, an advisory panel of the US Food and Drug Administration (FDA) meeting on October 8, 2014, concluded that—despite strong evidence of safety—it could not recommend in favor of efficacy. Overall, the panel did not express strong support for the relative risk-benefit ratio of the device.
The Circulatory System Devices Panel has met twice previously since 2009 to review and vote on the premarket approval submission of Watchman (Boston Scientific; Natick, MA). The most recent meeting, held in December 2013, resulted in a 13-1 vote in favor of approval based on the panel believing in a reasonable assurance of device safety and effectiveness, with the probable benefit outweighing the probable risk. Despite the strong show of support, the FDA requested that the panel meet again to review updated datasets from PREVAIL and PROTECT AF.
However, while the latest advisory panel, led by Richard Page, MD, of the University of Wisconsin School of Medicine and Public Health (Madison, WI), voted unanimously that the device was safe (12-0), its members were split 6-6 on the matter of efficacy. Dr. Page broke the tie by voting no. The next surprise came when the panel considered the question of risks vs benefits and responded 6-5 in favor with 1 abstention.
Panel member David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), told TCTMD in a telephone interview that this was the most difficult advisory meeting in which he has ever participated.
“The extent to which I struggled with my decisions at the time of the vote was no less [than the] struggle I had at 8:00 AM when the meeting began,” he said. “Myself and many other panel members did not believe in the proposed indication, yet at the same time we felt there was a reasonable assurance of risk-benefit ratio to have this device available to patients in the United States. But exactly how that label is worded—and in which patients [Watchman] should be used—will be the next challenge should the FDA take this panel’s advice.”
Ischemic Stroke Incidence Troubling
The labeling indication proposed by Boston Scientific states that the device is intended “to prevent thromboembolism from the left atrial appendage” and “may be considered for patients with nonvalvular atrial fibrillation who, based on CHADS2 or CHA2DS2-VASc scores, would be recommended for warfarin therapy to reduce the risk of stroke and systemic embolism.”
In the end, Dr. Kandzari said the panel was troubled by the numerical excess of ischemic stroke that emerged in the device arm of PREVAIL given that the Watchman is intended to reduce it.
“The dilemma became centered around the device actually demonstrating that it was doing what it was intended to do,” he said, adding that the expectation had been that the updated data from PREVAIL would be the same as “what we had seen previously when we were reviewing a slice of the data [in 2013].” But that did not turn out to be the case.
The multicenter PREVAIL trial randomized subjects with nonvalvular A-fib who were eligible for warfarin to Watchman implantation plus short-term (45 days) warfarin therapy or warfarin alone. When the advisory panel met in 2013, there had been 6 ischemic strokes (5 in the Watchman group and 1 in the control group).
Yet by January 2014, 6 additional ischemic strokes were reported, all in the Watchman arm, for a total of 11 vs 1 in the control arm. Furthermore, between January and June 2014 there were 2 additional ischemic strokes in the Watchman arm bringing the total to 13.
Dr. Kandzari described the panel’s sense that, “we were moving further away from the expected benefit with the Watchman device.”
Plaguing the Watchman trials as well as the advisory panel is the use of complicated modeling and Bayesian trial design. Even with a statistician on the panel to interpret for them, Dr. Kandzari said, “situations like this should make us rethink how they do the analyses for these trials [because] when the results are disparate, Bayesian makes it much more difficult to interpret.”
Second-line Therapy Proposed
The bottom line, Dr. Kandzari said, is that while the majority of the panel believes the device is important and does have a role in clinical practice, the proposed labeling cannot stand as currently written.
Many on the panel suggested that Watchman should be offered as second-line therapy rather than as an alternative to warfarin, he reported. Another suggestion—which could be difficult for the FDA to interpret—is that clinical choice should play a role, with patients receiving full disclosure about risks vs benefits.
Whether the FDA will regard
the split votes by the panel as unfavorable is uncertain, but depending on what
the agency decides, there likely will be considerable conditions placed on how
and in whom it is used, he concluded, adding that eventual coverage decisions
by CMS and third-party payers may highly restrict Watchman use.
US Food and Drug Administration. Boston Scientific WATCHMAN left atrial appendage closure therapy [executive summary]. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM417199.pdf. Published October 7, 2014. Accessed October 9, 2014.
- Dr. Kandzari reports receiving research/grant support from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic and serving as a consultant to Boston Scientific and Medtronic.