TAVR Cerebral Embolic Protection Trial Stopped Prematurely

LONDON — Two years after the large multinational PROTECTED TAVR trial failed to associate a cerebral embolic protection (CEP) device with significant protection from stroke in patients undergoing transcatheter aortic valve replacement (TAVR), a second multicenter trial with a similar design was stopped at an interim analysis for futility. 

The Data Monitoring Committee (DMC) of the BHF-PROTECT-TAVI trial determined “there is little prospect of demonstrating a benefit in the primary endpoint.” Moreover, given the confidence intervals, the data “could not rule out the potential for harm.”

With 7490 patients enrolled at the time of the interim analysis, the BHF-PROTECT-TAVI was even larger than the 3000-patient PROTECTED TAVR trial. As in the previous trial, patients undergoing TAVR were randomized to CEP or no CEP with no CEP considered the standard of care.

Based on the interim analysis, the DMC released a statement on October 24 to announce the trial’s termination. The specific data leading to this decision are not expected to be published until early 2025.

Primary Endpoint was Acute Stroke

The open-label BHF-PROTECT-TAVI trial, employing the acronym TAVI (transcatheter aortic valve implantation) rather than TAVR, enrolled patients with aortic stenosis and a scheduled TAVR procedure. Most centers offering TAVR in the United Kingdom. participated. The primary endpoint was stroke within 72 hours of the TAVR procedure.

The results of PROTECTED TAVR trial unexpected. The CEP device used in this study and in BHF-PROTECT-TAVI, was approved by the US Food and Drug Administration (FDA) in 2017 on the basis of evidence that it can capture perioperative debris, preventing it from reaching the cerebrovascular circulation. This debris is a known cause of TAVR-related stroke, even if clinical benefit was proven in a randomized trial. 

In fact, despite a neutral result, the authors of PROTECTED-TAVR note “the results may not rule out a benefit.” This type of phrasing is unusual for a study that did not meet its primary endpoint, and it was criticized by independent experts.

PROTECTED TAVR Given a Positive Spin

In a 2022 MEDSCAPE commentary John M. Mandrola, MD, an electrophysiologist affiliated with Baptist Health, Louisville, Kentucky, characterized this wording as “positive spin.”

Even when trials that miss their primary endpoint by very thin margins, citing an example of one with a P value of.6, Mandrola questioned the decision to preserve the potential for benefit based on a secondary outcome. 

The P value for the primary outcome of PROTECTED TAVI was.3, which is a substantial distance from a probable benefit. In addition, there was no significant difference between groups for all-cause death or a composite outcome of stroke, transient ischemic attack and delirium. 

There was a difference in disabling stroke (0.5% vs 1.3%) that favored CEP statistically by the fact that the 95% CI for the advantage remained just below the line of unity (−1.5 to −0.1), but Mandrola pointed out that this specific positive result was one of 15 secondary endpoints. He indicated the positive spin was not justified.

Not even a month ago, a post-hoc “exploratory” analysis of PROTECTED TAVR added some fresh positive data. Presented the principal investigator, Samir Kapadia, MD, Chairman, Department of Cardiovascular Medicine, these data showed statistically significant benefits of CEP over no CEP when the data from US centers were separated from those of centers outside of the United States.

In this analysis, simultaneously published in JAMA Cardiology, a major discrepancy was found between the device performance among US centers and those elsewhere. In the US, CEP relative to no CEP achieved a benefit on both the primary endpoint (2.6% vs 1.3%; P =.045) and the secondary outcome of disabling stroke (0.4% vs 1.5%; P = .018)

The higher stroke rates among those randomized to CEP outside of the United States explains the overall trial result (3.7% vs 3.3%; P = .662). Disabling stroke rates were numerically lower in the CEP group (0.7% vs 1.0%; P = .545).

There are many potential explanations for this disparity, such as differences in how US patients are selected for TAVR or how the device is deployed. However, Kapadia reported at the TCT that he is inclined to trust the US findings and continues to consider the FDA-approved CEP device when performing TAVR. 

Contacted after TCT for a comment about the early termination of BHF-PROTECT-TAVI, Kapadia reiterated that there is a need to understand the discrepancy between patients treated in or outside of the United States in his own study and now to take a closer look at the details of the BHF-PROTECT-TAVI trial in relation to PROTECTED TAVR.

“We are planning to have a combined analysis of these data to better understand which patients benefit from this device,” Kapadia told Medscape Medical News. He indicated that the release of the BHF-PROTECT-TAVI will be critical to moving forward.

“It is important to understand the details of the data,” Kapadia said. Although the value of the routine use of CEP is less clear now that there are two neutral trials, he remains optimistic that a role for CEP in preventing TAVR-related stroke will be eventually proven.

The BHF-Protect-TAVI trial, like PROTECTED TAVR, received funding from Boston Scientific. Mandrola and Kapadia reported no potential conflicts of interest.