Presumed Clinical Benefits of TAVR Cerebral Protection Remain Unproven

BOSTON -- Cerebral embolic protection (CEP) again came up empty in preventing strokes after transcatheter aortic valve replacement (TAVR) despite safely capturing embolic material dislodged during the procedure, a large randomized trial found.

In the 3,000-person PROTECTED TAVR trial, the sentinel dual-filter system produced no significant reduction in periprocedural strokes compared with control cases without the device (2.3% vs 2.9%, P=0.30), according to Samir Kapadia, MD, of Cleveland Clinic.

Kapadia added that no subgroup seemed to get less strokes from protected TAVR. "Stroke remains unpredictable," he said in a presentation at the Transcatheter Cardiovascular Therapeutics (TCT) meeting hosted by the Cardiovascular Research Foundation. The results were simultaneously published in the New England Journal of Medicine (NEJM).

This might be disappointing for clinicians who had hoped to narrow down CEP candidates based on this trial. It had been thought that by valve anatomy or procedural characteristics, certain patients would at least benefit more than others, commented Robert Cubeddu, MD, of Naples Heart Institute in Florida, at a TCT press conference.

There was some redemption in Sentinel's association with fewer disabling strokes after TAVR (0.5% vs 1.3%, P=0.02), with the number needed to treat to prevent one disabling stroke being 125 patients.

But this is not a definitive finding and will need to be replicated, cautioned John Carroll, MD, of University of Colorado School of Medicine/Anschutz Medical Campus in Aurora, and Jeffrey Saver, MD, of David Geffen School of Medicine at the University of California Los Angeles, in a NEJM editorial.

Otherwise, the trial produced no substantial differences in mortality rates or the combined endpoint of stroke, transient ischemic attack, or delirium. Incidence of acute kidney injury was the same 0.5% between groups.

PROTECTED TAVR comes years after the much smaller SENTINEL trial, in which CEP successfully filtered out histopathologic debris in 99% of patients but failed to significantly reduce new lesion volume in protected brain territories or reduce major adverse cardiac and cerebrovascular events.

Nevertheless, FDA approved the Sentinel in 2017 on the presumption that catching debris before it reaches the brain should theoretically benefit patients undergoing intracardiac procedures. Since approval, however, real-world data continues to show no stroke benefit with the device.

The adoption of CEP has been variable and slow to proliferate. When asked how the new data would affect clinical practice at the press conference, the panelists broke into a few chuckles.

Michael Young, MD, of Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, said the study "muddies the waters for programs that are more medium-volume. A number needed to treat of 125 is going to be a tough sell for some of those programs to ubiquitously use that for all their patients."

"A lot of it rolls down to cost and we need to be realistic about that," Cubeddu said. "In many [TAVR] programs across the country, the margins of sustainability and cost and revenue are just marginal."

He suggested it would be interesting to see how the Centers for Medicare & Medicaid Services (CMS) interprets the results of PROTECTED TAVR.

The postmarket trial was conducted at 51 centers in North America, Europe, and Australia. Investigators randomized transfemoral TAVR candidates to the procedure with or without CEP.

Neurologic examinations were performed on all the patients at baseline and after TAVR. Routine neuroimaging was not performed to identify covert brain infarction.

Participants averaged age 78.9. There was a greater proportion of women in the protected group (42.0% vs 37.8% of controls), whereas Society of Thoracic Surgeons surgical risk was similar between groups (3.4% vs 3.3%).

The Sentinel was successfully deployed in 94.4% of attempts.

The trial's primary endpoint was stroke within 72 hours after TAVR or before discharge. Carroll and Saver warned that the counting of these events may have been flawed in the study.

"An underdetection of stroke events may have occurred because neurologic assessments were not always performed by experienced neurologists and because a formal structured interview to determine the presence of stroke symptoms was not used. A small amount of overcounting of end-point events may also have occurred owing to the use of a nonstandard approach of classifying asymptomatic covert infarctions as strokes," they wrote.

As for safety, only one patient had a vascular complication at the access site, according to Kapadia.

"The safety of the device and its possible effect on disabling strokes provide a ray of hope, but the concern persists that CEP, approved and marketed on the basis of surrogate outcomes, may not actually provide a clear and incontestable clinical benefit," according to Carroll and Saver.

In any case, PROTECTED TAVR may be a testament to how much TAVR has matured since it was first developed in 2002.

"The fact that the negative results of the study are in part due to the low incidence of stroke events in the control group conveys good news -- stroke frequency without CEP is low in contemporary practice as compared with the early experience with TAVR and is likely due to operator experience, technical refinements to procedural equipment, and the use of TAVR in healthier patients," the editorialists said.