PREVAIL Published: Watchman Safe, Meets One of Two Efficacy End Points

June 30, 2014

ROCHESTER, MN – The PREVAIL study, a clinical trial evaluating the safety of the Watchman (Boston Scientific) left atrial appendage (LAA) closure device in the treatment of patients with nonvalvular atrial fibrillation (AF), is now published in the Journal of the American College of Cardiology[1].

Appearing online June 30, 2014, the PREVAIL study, a controversial study that was pulled from the late-breaking clinical-trials session at the American College of Cardiology 2013 Scientific Sessions after Boston Scientific broke an embargo and announced the results in advance of the presentation, met the primary end point for safety and one of the two primary end points for efficacy.

"In this trial, LAA occlusion was noninferior to warfarin for ischemic stroke prevention or systemic embolism [more than seven] days postprocedure," write Dr David Holmes (Mayo Clinic, Rochester, MN) and colleagues in the journal. "Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms."

A Brief Roundup of the Results

Reported extensively by heartwire when it was presented in 2013, the publication results are essentially unchanged from the presentation. As they said at the time, the PREVAIL investigators note that procedural safety has improved significantly since the device was first tested in the PROTECT-AF study. In PREVAIL, the implant success rate was more than 95%, up from 91% in the PROTECT-AF study.

The main safety end point—seven-day occurrence of death, ischemic stroke, systemic embolism, and procedure- or device-related complications requiring major cardiovascular or endovascular intervention—occurred in 2.2% of patients who received the device and met the study's statistical definition for success.

The first efficacy primary end point was a comparison of the composite of stroke, systemic embolism, and cardiovascular/unexplained death among those who received the device compared with historical rates based on data from PROTECT. In PREVAIL, the Watchman device failed to demonstrate noninferiority on the first co–primary end point.

Co–primary End-Point Efficacy (stroke, systemic embolism, and cardiovascular/unexplained death)

Watchman device, 18-mo rate Control, 18-mo rate Rate ratio (95% CI)
0.064 0.063 1.07 (0.57–1.89)*
*Co–primary end point misses noninferiority criteria (upper bound set at <1.75)

The second efficacy end point—the comparison of ischemic stroke or systemic embolism occurring more than seven days postrandomization—did meet the criterion for noninferiority.

For the investigators, the clinical trial "provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with nonvalvular AF who do not have an absolute contraindication to short-term warfarin therapy."

Editorialist Offers Some Caveats

In an editorial[2], Dr Randall Lee (University of California, San Francisco), like the investigators, notes that one of the reasons the PREVAIL trial did not achieve noninferiority criteria for one of its co–primary end points was the low event rate in the control group. Despite the accumulating evidence showing that LAA exclusion is effective for reducing the risk of stroke in nonvalvular AF, Lee says the procedure "should not be considered universally as a substitute for oral anticoagulation therapy."

The new oral anticoagulants, for example, provide equivalent and in some cases superior benefit for the prevention of stroke compared with warfarin and are also associated with less bleeding risk, he notes.

"The initial embolic risks and adverse events associated with the Watchman device implantation cannot outweigh the long-term bleeding risks of the newer oral anticoagulation drugs," writes Lee. Also, he notes that until more data are available in high-risk patients—the elderly, those with a prior stroke, and those with renal dysfunction—the "decision to treat them with an LAA occlusion device instead of oral anticoagulation therapy should be made on the basis of the patient's overall health, ability to tolerate oral anticoagulation therapy, procedural risks, and the operator's experience."

Regarding the rate of thrombus formation, which was 4% in PREVAIL, and the potential for late thrombus formation, Lee recommends transesophageal echocardiography (TEE) at 45 days to assess for possible leaks and thrombus before discontinuing warfarin.

Three Times Through the FDA Regulatory Hoop

Despite the PREVAIL results and those of PROTECT, which preceded it, the Watchman device is not expected to be available to US physicians any time soon. In fact, the device has been through the regulatory ringer, and more scrutiny is to come.

In 2009, after the publication and presentation of the PROTECT-AF study, a Food and Drug Administration advisory panel voted 7-5 in favor of approving the device for closure of the LAA in patients with AF. Following the tepid recommendation, however, the FDA issued a complete response letter requesting another study to confirm the safety and efficacy. This led to the PREVAIL study and another go-round with the FDA advisory committee. With the second panel meeting, the advisory committee voted 13 to 1 that the benefits of the Watchman device outweighed the risks.

Despite the two positive votes from the FDA advisory committee, Boston Scientific recently announced that the FDA is requesting a third advisory panel meeting for the Watchman device. That committee meeting is as yet unscheduled, so even if the third panel meeting is positive and the FDA approves LAA occlusion for the prevention of stroke, the Watchman wouldn't be available to US physicians until at least 2015.

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 currently available in Europe.

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