Shelley Wood

October 29, 2013

SAN FRANCISCO, CA — Use of the self-expanding Medtronic CoreValve transcatheter aortic valve in the CoreValve Extreme Risk pivotal trial led to some of the lowest stroke and paravalvular leak rates seen in any transcatheter aortic-valve replacement (TAVR) study to date, investigators said today.

The trial, presented here at TCT 2013 by Dr Jeff Popma (Beth Israel Deaconess Medical Center, Boston, MA) also met its primary end point of reduction in all-cause death or major stroke; as expected, however, use of the device was associated with pacemaker implantation in more than one in five patients.

The CoreValve Extreme Risk trial was originally planned to randomize patients 2:1 to transfemoral CoreValve implantation or best medical care (including valvuloplasty). But as Popma explained, those plans were sidelined following the 2010 release of the PARTNER B results using the Edwards Sapien device. Following PARTNER B, there was no longer equipoise on the part of investigators, and it was no longer ethically acceptable to treat valve-eligible patients with medical care alone.

Dr Jeff Popma

Instead, drawing on valvuloplasty trials, as well as the most conservative estimates of mortality in the medical-care-only cohort in PARTNER B, the FDA and trial investigators agreed to redesign the study as a single-arm trial with an objective performance goal defined as reduction in death/major stroke of 43%.

In all, 471 extremely high-risk patients were treated with the CoreValve; all-cause mortality was 7.9% at 30 days and 24% at 12 months.

Stroke, one of the most talked about—and feared—complications of TAVR, occurred in 2.4% of patients at one month and just 4.1% per year. By way of comparison, in PARTNER B, 30-day and 12-month stroke rates were 5% and 7.8%, although Popma cautioned strenuously against "throwing up the numbers side by side."

Paravalvular Leaks

Paravalvular-leak (PVL) rates were also relatively low, with just 11.5% of patients having moderate or severe PVL at one month, and strikingly, noted Popma, that rate improved over time. By one year, only 4.1% of study participants still had paravalvular leak or, expressed in another way, 80% of patients with moderate PVL at one month had seen a reduction in the severity of that leak by 12 months. No patients progressed from moderate to severe over the course of the study.

Of note, however, seven patients (1.6%) had severe PVL at hospital discharge, and mortality in these patients was extremely high, at 86%.

"That tells us that we have to be very aggressive at the time of implantation" and not to accept this degree of PV leak, he told heartwire . "The lesson we learned here . . . is that there is a very dismal mortality rate in these patients." Operators who see this need to "do something" to fix this during the initial implantation, either implant another valve or perform a repeat dilatation. "That is our call to action," he said.

Dr Michael Mack

During a morning press conference, Dr Michael Mack (Medical City Dallas Hospital, TX) pressed Popma on this improvement in PVL, something he called "a little bit eye-opening" since it hasn't been seen in other trials.

Popma replied noting that all patients had undergone CT imaging to help with valve sizing. As well, he believes the self-expanding nitinol frame of the CoreValve design likely also played a role. "It's a remarkable finding and needs to be confirmed."

Dr Ajay Kirtane (Columbia University, New York, NY) also made the point that the number of patients undergoing echocardiography at one month was different from the number who received echos at 12 months—so it is important that the right "analyses get done."

Which Device, Which Patients?

Popma was reluctant to speculate just how operators might choose one valve over another, assuming the CoreValve gains US approval. The Sapien was approved for use in high-risk, nonsurgical patients in 2011, and both the Sapien and CoreValve have long been in use in Europe.

Popma preferred to predict that the CoreValve would help expand the pool of patients who could be treated in the US, because of the smaller sheath size as well as the broader range of annular sizes that the CoreValve offers. He also hinted that the CoreValve, potentially because of its self-expanding design, and given the low rates of PVL seen in this study, might be the better choice of valve "in those borderline cases where you can't tell the right size."

On the other hand, as has long been seen with the CoreValve, pacemaker implantation was required in a full 22.2% of patients—a factor that might swing device choice in the other direction in certain patients. Pacemaker implants were not, however, associated with decreased survival at one year, Popma noted.

Dr Ajay Kirtane

Also asked how to choose between the two transcatheter valves, Mack said he, too, didn't want to answer the question, noting that he has no experience with the CoreValve, but agreed that the smaller sheath size and larger annulus size will certainly be factors.

As for "everyone in the middle" and what device might be best, Kirtane added, "we still have to sort that out."

In other findings, major vascular complications with the CoreValve were 8.3% at one month and 8.5% at one year. Nine out of 10 patients saw their heart-failure symptoms improve by at least one NYHA class at 12 months. Quality-of-life scores also showed improvement.

In a surprise announcement, the FDA said today that, having reviewed the CoreValve Extreme Risk data, it has all the information it needs to evaluate the device in this group and will not be calling on an external advisory committee. Popma noted in his presentation that he hopes to have results on the parallel CoreValve trial—studying the device in high-risk patients who are also eligible for surgery—in time for the 2014 American College of Cardiology meeting.

Popma has previously disclosed receiving clinical research grants from Abbott Laboratories, Boston Scientific, Cordis, and Medtronic and serving as an advisor or consultant for Abbott Laboratories, Boston Scientific, and Cordis.

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