Clear Stroke Benefit Eludes Embolic Protection: PROTECTED TAVR Clear Stroke Benefit Eludes Embolic Protection: PROTECTED TAVR

The Sentinel cerebral embolic protection (CEP) device failed to reduce the overall stroke rate in patients undergoing transcatheter aortic valve replacement (TAVR) in the largest TAVR trial to date, further calling into question its clinical utility.

The primary outcome of stroke at 72 hours or before discharge occurred in 34 of 1501 patients with CEP and 43 of 1499 patients without (2.3% vs 2.9%; difference, −0.6 percentage points [95% CI, –1.7 to 0.5 percentage points]; P = .30).

There were 8 disabling strokes with the debris-capturing device vs 20 with unprotected TAVR (0.5% vs 1.3%; difference, −0.8 percentage points [95% CI, –1.5 to –0.1 percentage points]; P = .02).

The number needed to treat to prevent one additional disabling stroke was 125, Samir Kapadia, MD, Cleveland Clinic, Ohio, reported in a late-breaking session at Transcatheter Cardiovascular Therapeutics (TCT) 2022.

“Remember these patients are 70 to 80 years of age, trying to enjoy their life in the later part of their years and they’re looking for a good quality of life … so if you can prevent even one disabling stroke, it is very meaningful,” he told theheart.org | Medscape Cardiology.

Notably, subgroup analyses were unable to identify patients in whom overall stroke rates would be preferentially lower with embolic protection. “If you are going to say, okay, which patients are we going to use the Sentinel based on this particular study, we did not find a specific high-risk group,” he said.

Nevertheless, Kapadia concluded his presentation by saying that as a clinician, not a trialist, “CEP with the Sentinel device should be considered for all patients undergoing TAVR for reducing disabling strokes.”

The long-awaited results were published simultaneously in the New England Journal of Medicine.

Although PROTECTED TAVR is a negative trial, “a disabling stroke rate of less than 1% is still an important finding” that will resonate with patients, Kendra Grubb, MD, surgical director of the Structural Heart & Valve Center, Emory University, Atlanta, Georgia, commented to theheart.org | Medscape Cardiology.

“Strokes are absolutely devastating to our patients and, especially when you look at the age demographic of this study, over 70-year-old patients, for many of them a stroke and having to live with stroke is worse than death,” she said.

In terms of changing practice, Grubb said centers that use CEP will likely justify their practice with the reduction in disabling stroke, whereas centers that don’t use CEP will point to the missed primary endpoint. “We don’t have clearly defined patient populations that will benefit, so it just supports what we are already doing.”

About 2% to 3% of patients have a stroke after TAVR, but whether CEP use provides a clinically meaningful impact has been unclear.

Sentinel was approved by the U.S. Food and Drug Administration in June 2017 based on data from the SENTINEL IDE trial showing the device captured debris in 99% of patients and a trend toward lower new cerebral lesion volume.

Medicare does not fully reimburse for use of the device, however, and U.S. registry data show CEP was used in just 13% of TAVR procedures in late 2019.

Existing Beliefs

PROTECTED TAVR randomly assigned 3000 patients (mean age, 78.9 years) in a 1:1 ratio to undergo TAVR with or without Sentinel CEP (Boston Scientific) at 51 centers in North America, Europe, and Australia. The patients were evaluated before and after by a neurologist, and events were independently adjudicated.

Operative risk was evenly divided in both groups, with roughly a third of patients each at extreme/high, intermediate, and low risk. The mean CHA2DS2-VASC score was 4.2.

The device was delivered in 99.4% of attempted patients, with no major complications.

At 72 hours or discharge, there was no difference between the Sentinel and control groups in all-cause mortality (8 vs 4), the safety composite of all-cause mortality and stroke (41 vs 45), or acute kidney injury (8 vs 7). There was one CEP access site-related vascular complication.

Nondisabling strokes were reported in 1.5% of controls and 1.7% of CEP patients (P = .67). As expected, most disabling strokes were ischemic (17 vs 6), with few symptomatic hemorrhagic strokes (3 vs 2).

Most strokes were periprocedural and identified within the first day, Kapadia noted. Among controls, 12 strokes were in uncomplicated TAVR cases and areas that would have been protected had the Sentinel been used. One of the 8 disabling strokes in the CEP group occurred in a protected vessel in an uncomplicated TAVR.

Panelist Steven R. Messe, MD, professor of neurology at the Hospital of the University of Pennsylvania, Philadelphia, who was involved with PROTECTED TAVR, also said preexisting attitudes will influence how the results will influence practice but that “reducing disabling strokes is the holy grail in neurology.”

That said, the number needed to treat of 125 is “somewhat high, and I think that’s important and a cost consideration, given that it’s clearly safe,” he added.

Panelist Anita Asgar, MD, an interventional cardiologist at the Institut de Cardiologie de Montreal, Quebec, Canada, said her institution only occasionally uses the device and expressed disappointment that the trial did not provide any guidance on who would benefit from the device. “For us, cost is going to be a huge issue.”

Adding to the discussion, David J. Cohen, MD, St. Francis Hospital, Roslyn, New York, and Cardiovascular Research Foundation in New York City, said it’s important to remember that disabling stroke was one of many secondary endpoints in a negative trial with a P value of .02.

“So our confidence in that 125 is pretty wide and might even include zero or infinite,” he said. “A lot of the impact on practice is really just going to depend on people’s almost emotional, or Bayesian, interpretation of that finding, do you believe it or not.'”

Cohen highlighted the subgroup analyses and said, “I’ve said for a very long time, and I think this trial reinforces it, that there’s only two right ways to use embolic protection in TAVR: for everybody or for nobody. In between doesn’t work, and I think this trial showed that pretty well.”

Alexandra Lansky, MD, professor of medicine in cardiology at Yale School of Medicine, New Haven, Connecticut, had a somewhat different interpretation of the findings.

“Yes, you missed your primary endpoint, but it’s a 20% reduction in terms of the relative benefit from your treatment and when you look at the disabling stroke, which is a component of the primary endpoint, you’re looking at 60% reduction in disabling stroke, which is extremely meaningful in terms of prognosis, the implications for patients, et cetera,” she said. “I completely agree with your implications; this is not something we cannot completely ignore.”

Lansky questioned whether the investigators took into account the severity of stroke, given the competing risk for mortality in disabling strokes at 30 days, and pointed out that U.S. centers appeared to have lower overall and disabling stroke rates, despite a striking consistency among the various subgroups.

Kapadia replied that National Institutes of Health Stroke Scale  scores were fairly higher in disabling strokes but that they did not find a competing risk for mortality at 30 days. He said they were at a loss to explain the U.S. results, but “this is an important thing to investigate further.”

In an accompanying editorial, John D. Carroll, MD, University of Colorado, Denver, and Jeffrey L. Saver, MD, David Geffen School of Medicine, University of California Los Angeles, say the trial “strikes a serious blow” to the hope that the Sentinel device would have a definitive effect on TAVR-related strokes.

“The ‘smoking gun’ of captured debris was not associated with high-quality evidence of stroke prevention,” Carroll writes. “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.”

Professor Bernard Prendergast, MD, St. Thomas’ Hospital and Cleveland Clinic London, United Kingdom, commenting during the panel discussion that the data won’t be sufficient to convince the National Health Service to reimburse for use of the Sentinel device but that further insights will be forthcoming from the ongoing British Heart Foundation PROTECT-TAVI trial, which is testing the device in 7000 patients, and a mandated meta-analysis with data from PROTECTED TAVR.

When the panelists were asked whether they would use the device for a loved one undergoing TAVR, a show of hands revealed that all but one panelist, Asgar, said they would —  a tally similar to that when approval of the device was first debated.

The study was funded by Boston Scientific. Kapadia reports grant/research support from Boston Scientific and stock, shareholder, equity with Anteris and Navigate. Study chair Martin Leon, MD, founded TCT and the Cardiovascular Research Foundation. Grubb is a consultant for Boston Scientific, Medtronic, Edwards Lifesciences, Abbott, and Gore. Grubb reports consultant fee/honoraria/speaker’s bureau participation with Boston Scientific, Ancora Heart, W.L. Gore & Associates,  OpSens,  HLT, Edwards Lifesciences, Medtronic,  and Abbott Vascular. Messe reports grant support/research contracts with W.L. Gore & Associates and Terumo Medical  and consultant fee/honoraria/speaker’s bureau participation with Boston Scientific. Asgar reports grant support/research contracts with Abbott Vascular and consultant fee/honoraria/speaker’s bureau participation with Medtronic, Edwards Lifesciences, W.L. Gore & Associates. Cohen reports grant support/research contract with Boston Scientific, Edwards Lifesciences, Medtronic, Abbott Vascular, Ancora Heart, Volcano Corporation, Svelte, Corvia, Cardiac Dimensions, HeartFlow, and Zoll Medical/Therox and consultant fee/honoraria/speaker’s Bureau participation with Medtronic, Abbott Vascular, and Boston Scientific. Lansky reports having no relevant disclosures. Carroll reports personal fees from Edwards LifeSciences, other from Edwards LifeSciences, other from Medtronic, outside the submitted work; and serving as chair of the Steering Committee of the STS-ACC TVT Registry, which gathers data on all US patients receiving FDA approved transcatheter valve therapies. Saver reports personal fees from Filterlex; grants from Edwards; and personal fees from Abbott, Medtronic, Bayer, Roche, Johnson & Johnson, Amgen, MIVI, Rapid Medical, and Novo Nordisk. Prendergast reports grant support/research contract with Edwards Lifesciences and consultant fee/honoraria/speaker’s bureau participation with Edwards, Abbott Vascular, and Medtronic.

Presented at Transcatheter Cardiovascular Therapeutics (TCT) 2022.

N Engl J Med. Published online September 17, 2022. Abstract, Editorial

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