CardioExchange Archive

The FDA’s Circulatory System Devices advisory panel gave an extremely cautious endorsement on Wednesday to Boston Scientific’s Watchman device, a novel catheter-delivered left atrial appendage closure device for people with atrial fibrillation. They signaled that although they thought the device should be made available they also thought that there should be significant restrictions on its use.

The panel wrestled throughout the day with a fundamental problem: combined data from the two clinical trials, PROTECT AF and PREVAIL, showed clearly that Watchman was not equivalent to warfarin for the chief indication of stroke reduction in the study population. Furthermore, in clinical trials patients who received the Watchman were compared to patients taking warfarin. But there was a strong sentiment among panel members that the device should be available only to AF patients who are eligible for warfarin but don’t want to take it and, perhaps also, for patients who are not eligible for warfarin therapy. The problem, of course, is that neither of these patient groups was studied in the clinical trials.

Panel members delivered a complex message to the FDA regulators who will ultimately decide the fate of the device. They unanimously agreed that the device was safe, but split 6-6 on the question of efficacy. The panel’s chair, Richard Page, broke the tie with a no vote. On the final and third vote on whether the risks outweighed the benefits, 6 panel members voted yes, 5 no, and 1 (former ACC president Ralph Brindis) abstained. But panel members were highly vocal in stating that their vote did not indicate in any way support for the actual proposed indication for stroke reduction in warfarin-eligible patients.

Panel members said that they wanted the FDA to craft a narrow and highly restricted indication. Summarizing the panel’s sentiment, Page said it was incumbent on the sponsor and the FDA to maximize the degree to which only appropriate patients would get the device. “It’s not an alternative to every warfarin eligible patient,” he said. Panel members and FDA staff discussed several possible measures to achieve this goal, including patient guides, a controlled rollout with limited device availability, the requirement that an independent physician sign off before the procedure, and a national registry.

Bram Zuckerman, the director of the FDA’s Division of Cardiovascular Devices, agreed that “if approved it would require continuous monitoring of appropriate use.”

Panel members were acutely aware of their difficult position. Said Page: “The problem is that the proposed indication — prevention of thromboemboslim — is no longer realistic, so a likely real world use is for the device to be used in a different population and not as a replacement for warfarin.” Patricia Kelly suggested that the Watchman “could be offered to patients who don’t want to take warfarin, but they would need to be told that it is not considered equivalent to warfarin.”

The panel struggled with the differences between first-line therapy and second-line therapy as well as warfarin-eligible, warfarin-intolerant, and people who just don’t want to take warfarin. Said Page: “Every patient in Watchman clinical trials was warfarin eligible but now the only possible indication may be for warfarin-ineligible patients.”

David Kandzari said that even a “second line indication would be hard when both primary efficacy endpoints were missed.” Page noted that it would be difficult to make sure that it was available only as a second line.

Given the failure of the trials to demonstrate noninferiority, Rick Lange commented: “I’m just a simple guy. If something is not noninferior then it’s inferior.” He then asked “how do we recommend an inferior therapy to patients?”

Ultimately, however, the panelists agreed with Page that the “totality of data argues in favor of clinical choice,” although they were unable to define that choice with any precision.

Watchman has been under development for more than a decade and its approval has twice been postponed by the FDA. Most of the controversy over the device has centered around two clinical trials. Although the initial PROTECT AF trial was technically a positive trial, it had a number of important weaknesses and in 2010 the FDA required the company to perform another clinical trial to demonstrate the long-term safety and effectiveness of the drug. The PREVAIL trial was then designed to supplement PROTECT AF. The initial results appeared somewhat promising, but the complicated trial design, with three co-primary endpoints and a novel and difficult-to-understand Bayesian trial design, led to considerable controversy. Based on complete results from the trial, FDA reviewers and panel members agreed that it failed to show that Watchman was an acceptable alternative to warfarin.