Watchman Device Gets Big Nod From FDA Advisors

December 11, 2013

GAITHERSBURG, MD (updated December 12, 2013) — A second time around the regulatory block appears to be the charm for the Watchman(Boston Scientific), an investigative device that can be used instead of warfarinto reduce the risk of stroke in atrial fibrillation (AF) patients.

An advisory committee voted almost unanimously in favor of the novel device, voting 13 to 1 on a question that asked the experts if the Watchman's benefits outweighed any potential risks. The advisory panel, led by Dr Clyde Yancy (Northwestern University, Chicago, IL), ultimately believed the device was a safe and effective treatment to prevent the embolism of thrombus from the left atrial appendage (LAA) and to reduce the risk of stroke in patients with nonvalvular AF.

"We've been treating atrial fibrillation since 1954 with warfarin, a drug meant for rats, and it's really a structural problem," said advisory panel member Dr Patrick Noonan (Scott and White Memorial Hospital, Temple, TX). "Now we have a device that really addresses this structural problem. We may look back in a few years when there are different iterations of the device or other devices, and this device may seem crude then, but we have to take the first step."

Dr David Yuh (Yale University School of Medicine, New Haven, CT) said the device "might not be as effective as Coumadin—that remains to be seen—but it's pretty damn close in terms of the curves that we've seen." On the whole, the Watchman device "represents a viable procedural alternative to Coumadin therapy," he added. "I know that many patients that I see will alter their ballot choice to get away from Coumadin, even if it means a reoperation. So I don't discount the impact that this will have on many patients."

Similarly, Dr Joaquin Cigarroa (Oregon Health and Science University, Portland) voted in favor of the Watchman on the question of safety, effectiveness, and the overall risk/benefit based "on the basis of the totality of the data, coupled with clinical context." He said the clinical trials supporting the Watchman device were well executed, even though there were some problems interpreting the data. "All trials have warts, we know that, and there is no perfect trial," said Cigarroa.

Second Time Around for Watchman at the FDA

The Watchman device seals off the LAA in the heart, which is the major source of stroke-causing thrombus in AF patients. It is implanted via a transseptal-catheter–based delivery system and is already available in Europe.

In 2009, the Circulatory System Devices Advisory Panel voted 7 to 5 in favor of approving the Watchman device for the closure of the LAA. The advisory panel recommendations were based on the results of the Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) trial, the pivotal premarket approval study. The results were first presented at the i2 Summit of the American College of Cardiology (ACC) 2009 Scientific Sessions and showed that that the Watchman device was associated with a reduction in hemorrhagic stroke risk vs warfarin, and all-cause stroke and all-cause mortality outcomes were noninferior to warfarin.

Nearly a year after the recommendation, however, the FDA requested an additional study to address some of the concerns with the PROTECT-AF study. This led to the PREVAIL study, with 407 patients who were randomized 2:1 to the device or long-term therapy with warfarin. With the PREVAIL trial, the FDA requested the inclusion of higher-risk patients, the exclusion of those on chronic clopidogrel therapy, and better anticoagulation in patients randomized to warfarin. Importantly, the FDA said that at least 25% of patients had to be enrolled by new operators and at least 20% enrolled at new investigation sites.

The clinical trial, as reported by heartwire , met two of three of its primary end points, including the safety end point and one of its primary efficacy end points, although it too was a controversial study. Slated for presentation at this year's American College of Cardiology meeting, the trial was yanked by program chairs at the 11th hour, after pre-embargo results were sent to an undisclosed number of industry analysts and journalists.

Regarding the 18-month combined efficacy end point of stroke, systemic embolism, and cardiovascular or unexplained death, the Watchman did not meet the statistical criteria for noninferiority. When researchers analyzed ischemic strokes or systemic embolisms that had occurred at seven days postrandomization, the Watchman did meet the criterion for noninferiority compared with warfarin.

Procedural success rates were improved in the PREVAIL trial and in a Continued Access PROTECT-AF (CAP) registry, up from 91% to approximately 95%. The improvement in procedural success and safety was attributed to an educational program undertaken by the sponsor to teach less experienced physicians how to safety insert the device.

Interpreting the Hard-to-Interpret Trials

To heartwire , panel member Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA) said that despite the overwhelmingly positive votes on safety, effectiveness, and risk, the panel grappled with how to interpret the efficacy of the Watchman device given the statistical modeling estimates used in the PREVAIL trial. As Dr Richard Lange (University of Texas, San Antonio), the committee's lone dissenter, pointed out throughout the discussion and vote, just 28% of the 18-month data were available for assessment, leaving the panel to make a decision about efficacy based on extended follow-up from PROTECT-AF, CAP, and PREVAIL.

"Although rates of ischemic stroke and systemic embolism were numerically higher with the WATCHMAN device, overall the panel believed the event rates in the device and warfarin arms were clinically similar," noted Kandzari in an email. "In addition, 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."

Dr Jeffrey Borer (State University of New York, NY) said the Watchman represents a very important treatment option for patients with AF, a segment of society that is growing as the population gets older. "Not all the desired information is available just yet, but the very comprehensive analyses by the sponsor and the FDA convinced me that it is reasonable to extrapolate from the data we have to approvability."


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