By Larry Haimovitch

Medical Device Daily Contributing Writer

March 13, 2013

SAN FRANCISCO — The 62nd Annual Scientific Session of the American College of Cardiology (ACC; Bethesda, Maryland) kicked off here early on Saturday morning, with a new and surprising turn in a series of unusual events that have surrounded the Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) trial.

The results from PREVAIL, sponsored by Boston Scientific (BSC; Natick, Massachusetts), were arguably the most eagerly anticipated trial at this meeting. It was scheduled to be the first trial to be reported on the first day in the Late Breaking Clinical Trial session. Early in the week leading up to ACC, the full data set, that is both safety and efficacy endpoints, were expected to be presented by the principal investigator, David Holmes, MD, Scripps professor of medicine at the Mayo Graduate School of Medicine, (Rochester, Minnesota).

However, in an extremely unusual and perhaps unprecedented action, just a few days before the scheduled presentation, BSC announced that only the  “acute procedural safety results” would be presented. No explanation was provided. A couple of days later, in another bizarre U-turn and possibly under pressure from the ACC, BSC reversed its position and said that the full results of the trial would end up being presented after all.

Finally, on Saturday morning, just hours before Holmes’ scheduled presentation, BSC put out a press release with the trial data, inadvertently violating the ACC’s strict rules about pre-release of clinical trial data. It appeared to be an innocent and unfortunate oversight, with the three-hour difference between the east coast (where BSC is headquartered) and the west coast (site of ACC meeting) likely causing the early release.

The week’s insanity was capped off by a terse statement from Beth Casteel, Media Relations Director of the ACC, who said: “The embargo has been broken on the PREVAIL study. The embargo is immediately lifted and PREVAIL will not be presented in the late-breaking clinical trial session or the (ACC) press conference.  The embargo was broken when Boston Scientific distributed the press release without embargo early this morning.” So, while the trial was not officially released, the full slide set was obtained by many in the media and the data was quickly disseminated worldwide.

The basic goal of PREVAIL was to alleviate lingering concerns about the safety and efficacy of the WATCHMAN left atrial appendage (LAA) closure device left over from the earlier Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) trial and the follow on continued access program. Data from PROTECT AF trial, which had been released at the ACC in 2009, showed encouraging efficacy results that met non-inferiority and showed a trend towards superiority of left atrial appendage closure over warfarin. However, safety was compromised by an excess of acute events, leaving the LAA arm with over 50% more safety events than the oral anti-coagulation drug therapy (warfarin) arm. Following a positive but lukewarm Circulatory System Devices Panel meeting also in 2009, the FDA in 2010 decided that another trial would be required to confirm the safety and efficacy of the WATCHMAN.

There were three key endpoints to PREVAIL: (1) Acute (seven day) safety results, which included acute occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention. This endpoint was met, based on a 2.2% event rate, which was within the prespecified criterion for the endpoint: (2) The two other co-primary endpoints were efficacy endpoints which compared the WATCHMAN arm to the control group (warfarin) at 18 months. Unfortunately, only 30 of 138 control patients and 58 of 269 device patients have been followed for 18 months.

The trial missed the second primary endpoint, the comparison between a composite of stroke, systemic embolism, and cardiovascular/unexplained death at 18 months. The 18-month rate was 6.4% in both groups. The third primary endpoint, which was a composite of ischemic stroke or systemic embolism occurring after day 7, was achieved. At 18 months the event rate was 2.53% in the device arm versus 2.01% in the control arm, which met the prespecified criterion for non-inferiority.

In its ill-timed press release, Boston Scientific stated that the trial showed that the “device continues to demonstrate positive clinical outcomes for patients with atrial fibrillation.”

Due to the embargo break, there was no formal presentation or press conference to discuss PREVAIL. However, in an impromptu meeting with a small cadre of reporters on Saturday afternoon, Holmes carefully explained the rationale for the trial design. In particular he discussed the use of a Bayesian adaptive trial design, which leveraged off of the PROTECT-AF trial data and reduced the number of patients needed to attain statistical significance.

Using a Bayesian design allowed the researchers to draw conclusions from the data, even though they had 18 month information from only 58 patients who received the device and 30 patients in the warfarin control group. There has been some debate in the cardiology community about whether this is a large enough cohort to draw accurate conclusions but this approach was apparently blessed by the FDA.

Holmes stated that the safety data in PREVAIL was “giantly better” than and “twice as good” as PROTECT-AF. With that goal met and one of the two primary efficacy endpoints achieved, Holmes said that “it is a real step forward” and he voiced cautious optimism that the FDA will approve it.

In a research note after the PREVAIL travails, Lawrence Biegelsen, senior analyst, medical devices of Wells Fargo Securities (New York) opined that “we think the likelihood of Watchman approval has been lowered to about 50-60% from 90%+ if all three PREVAIL endpoints had been met. Ultimately, we think FDA will require another advisory committee panel which could push approval out to 2014, best case scenario.”

In another interview with a few reporters, Gordon Tomaselli, MD, professor and director of the Division of Cardiology at the Johns Hopkins University School of Medicine (Baltimore) and immediate past president of the American Heart Association (Dallas) said that the safety data from PREVAIL makes him “less hesistant” to use the WATCHMAN for a “select group of patients who have no other options.”

“PREVAIL definitely allays some of my safety concerns,” he added.

Tomaselli estimated that about 5% of his patients with atrial fibrillation might be ideal candidates for the device, though he admitted that this pool may be shrinking with the FDA’s approval of three new oral anti-coagulation drugs in the past three years.

Accurately sizing the market potential for any new device or procedure is challenging but Biegelsen indicated that “we currently model U.S. Watchman sales of $38 million in 2014, increasing to $104 million in 2017, and worldwide Watchman sales of $29 million in 2013 and $159 million in 2017.

David Lewis, another well-regarded medical device analyst from the investment banking firm Morgan Stanley (New York) said in a note before the ACC that he believes the market potential to be about $150 million. In addition, Lewis noted that “. . . patient appetite for undergoing an interventional procedure to treat condition already well controlled by drug therapy is likely to be limited.”

Meanwhile, Boston Scientific officials have estimated the potential market at $500 million within five years. Ken Stein, chief medical officer of the company’s cardiac rhythm management group said “we are really optimistic about this . . .we see it as fitting a huge patient need and having a huge amount of data to support it.”

Boston Scientific acquired the developer of the WATCHMAN, Atritech (Plymouth, Minnesota) in January 2011 with an up-front cash payment of $100 million, with potential future milestone payments through 2015 worth up to an additional $275 million. These milestone payments were based on a combination of regulatory approvals (most likely PMA clearance) and the attainment of certain revenue levels. Atritech was founded in 2000 and had raised an estimated $100 million from the venture capital community prior to its purchase by BSC.

American College of Cardiology 2013

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